Irregular or absent menstrual cycles in PCOS

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By Gary Goldman

Too often I consult with young women whose menses have become erratic or have stopped all together. For some, the lack of cycles has them worried about their general state of health, while others are concerned about infertility.

Erratic or absent ovulation leads to menstrual irregularities. Anovulation can be confirmed by checking for progesterone levels that remain consistently low. Alternatively, this can be evaluated with static basal body temperatures. Erratic cycles should be followed with a menstrual diary. Primary amenorrhea refers to women who have never had a period, which will not be discussed here. Secondary amenorrhea refers to a lack of cycles in someone who has had them previously.

There are many causes of secondary amenorrhea. An evaluation should take into account a particular woman’s circumstances. Pregnancy should be ruled out with an HCG test. Premature ovarian insufficiency can be explored by looking for a substantial elevation of follicle stimulating hormone (FSH) and luteinizing hormone (LH). In the setting of anorexia, or extreme loss of body fat seen in athletes, very low FSH and LH levels approximating pre-menarche levels can be found.

Women with PCOS can make an insufficient amount of FSH in the granulosa cell and have a normal to high normal amount of LH, which is made in the theca cell. This can produce an increased LH to FSH ratio of greater than three when measured on day three of an ovulatory cycle. Elevated LH levels can give a false positive home urine ovulation test. These tests are designed to turn positive at a certain level indicative of the LH surge seen in normal ovulatory women, a level exceeded chronically without ovulation in some women with PCOS.

A pituitary microadenoma is considered in the setting of visual field changes, headaches, and bilateral milky nipple discharge; a prolactin level should be ascertained even if the woman is asymptomatic to exclude this concern. While nursing there is a physiologic elevation of prolactin which will also inhibit regular ovulation.

Thyroid dysfunction is another common reason for menstrual irregularities. A TSH, T3, and T4 form the basic evaluation, and further testing can be individualized including a reverse T3 and anti-thyroid antibodies.

An unusual cause of secondary amenorrhea is postpartum pituitary gland necrosis, which represents loss of the anterior pituitary gland. This often follows severe trauma or rapid blood loss. This can be suggested by an appropriate history and confirmed by a loss of pituitary stimulatory hormones, as well as suspicious findings on a pituitary MRI. Congenital adrenal hyperplasia can also be considered as a rare cause of secondary amenorrhea and can be screened with a 17-hydroxy-progesterone level.

Various medications can inhibit ovulation. If the patient recently stopped using the birth control pill, the hypothalamic clock of pulsatile secretion of gonadotropin releasing hormone can be altered, resulting in prolonged amenorrhea. Recent use of progestins, either by oral, subcutaneous, topical, or intramuscular depot can have a prolonged impact on menstrual regularity. Steroid use, antipsychotics, chemotherapy, antidepressants, blood pressure medications, and some allergy medications can also alter menstrual regularity. Once other reasons for amenorrhea have been ruled out, the diagnosis of exclusion is PCOS.

PCOS is characterized by menstrual irregularities, infertility secondary to anovulation, virilization, metabolic syndrome, and obesity. There is substantial variability in the severity of symptoms among affected individuals.

If the woman does not currently desire pregnancy and there is evidence of estrogen production, the goal is to protect the endometrium from long term unopposed estrogen stimulation; this can lead to endometrial hyperplasia and in the long-term to endometrial carcinoma. Endometrial evaluation is typically begun by sonogram. If appropriate, a progestin-induced withdrawal bleed can confirm estrogen stimulation. Endometrial biopsies are appropriate when the endometrium is abnormally thickened or non-uniform.

If she is not making estrogen, then we are concerned about long term adverse effects on bone and cardiovascular health. Screening for dyslipidemias is important, and a DEXA bone density study can be useful in some circumstances.

Whether a patient is or is not making estrogen, the most commonly prescribed, expeditious traditional therapy is the oral contraceptive pill (OCP), especially if there is also evidence of hyperandrogenism. OCP’s will protect the endometrium from adverse build-up. They help to stimulate bone osteoblast activity increasing the amount of bone matrix. Restoration of systemic estrogen helps to prevent premature degradation of vascular endothelium, though the pro-clotting effects of the OCP can rarely promote venous thromboemboli. OCP’s also increase SHBG, which helps to diminish hyperandrogenic symptoms when present.

Levonorgestrel containing IUD’s can also be used to maintain endometrial health and help to prevent endometrial hyperplasia or endometrial carcinoma.

If the woman desires pregnancy, then therapy is typically ovulation induction. In years past this had been performed by administering clomiphene citrate, subsequently with metformin, and then with metformin combined with clomiphene citrate. More recently, letrozole, an aromatase inhibitor, has been demonstrated to have the highest rates of success for inducing ovulation in the PCOS patient, and in 2018 American College of Obstetricians and Gynecologists recommended this as first line therapy.

If all of these orally administered medications fail, then we consider injectable gonadotropin therapy. Patients with PCOS have a higher rate of ovarian hyperstimulation syndrome with gonadotropin therapy, thus low dose protocols are often used. Another option is laparoscopic ovarian drilling. This procedure does not improve the metabolic abnormities of PCOS, but it does not increase the risk of multi-fetal pregnancies seen with gonadotropin therapy.

The functional medicine practitioner has a deeper selection of tools available to help achieve the patient’s goals. This typically begins with careful consideration of the patient’s diet, level of exercise and BMI. The majority of women placed on a healthy, anti-inflammatory diet will see reduced insulin secretion and higher rates of ovulation. As little as a 5 percent decrease in weight will restore menstrual regularity in over fifty percent of women.

Acupuncture has also been demonstrated to improve menstrual regularity and, in conjunction with in vitro fertilization (IVF), can improve pregnancy rates.

A multitude of supplements have been evaluated to improve ovulation and restore menses, as well as for their role in promoting a healthy pregnancy. Alpha lipoic acid (ALA), 400 milligrams daily, improves menstrual regularity in 75 percent of women, restores ovulation in 40 percent of women who are anovulatory, and improves oocyte quality during IVF. N- Acetyl Cysteine (NAC) reduces insulin resistance, increases ovulation, and reduces oxidative stress.

In addition, Metformin reduces insulin resistance, aids in weight loss, improves ovulation, and may reduce the risk of miscarriage, though this idea is controversial. Berberine acts similarly to metformin, reducing insulin resistance and improving ovulation. Quercetin acts synergistically with berberine and is also a potent anti-inflammatory. Myo-inositol, four grams daily, results in better oocyte quality in IVF, helps to improve menstrual regularity and helps to reverse anovulation. Melatonin, two milligrams daily, has been demonstrated to improve ovulation, follicular development, luteal function, and oocyte maturation.

Finally, Vitamin D supplementation, if deficient, has been shown to improve menstrual regulation. Tribulus terrestris has been shown to improve ovulatory frequency and may reduce the excessive cysts found within the ovary in PCOS.

Case Study

Melissa is a 22-year-old woman who has been followed by a local pediatric endocrinologist for hirsutism since menarche. She underwent an extensive workup for congenital adrenal hyperplasia which was negative, and she was told she has PCOS. She had serial lab studies demonstrating a low SHBG around 35, elevated total testosterone levels of about 50 and elevated free testosterone levels of about eight. Her FSH averages about five, and her LH averages about 16. Her DHEA is in the high normal range. The remainder of her labs are normal, including a fasting insulin and glucose, and hemoglobin A1c.

She complained of oily skin, thinning hair on her crown, acne on her face, back, and sternum, and increased thick hair on her lower abdomen, inner thighs, and wrists. She has had difficulty losing weight and had a BMI of 28. Her menses were infrequent, occurring about twice per year spontaneously. She has been treated with cyclic progestins to induce menses for any occurrence of amenorrhea great than two and a half months. She does not wish to become pregnant. Her last progestin-induced withdrawal bleed was two weeks ago.

I confirmed the physical findings she noted. I performed a transvaginal ultrasound which demonstrated a grossly normal uterus with a uniform six-millimeter endometrium. Both ovaries were enlarged to about 15 cubic centimeters and each contained greater than 25 follicles, all of which measured between six and nine millimeters.

Melissa and I had a lengthy discussion regarding her diagnosis of PCOS and the lifestyle, and medication, and supplements recommended for the condition. The primary lifestyle intervention was diet and exercise. Melissa said her diet consisted mostly of pizza and bagels with an occasional salad. We discussed a more appropriate modified Mediterranean diet and I introduced her to our nutritionist for further information, encouragement, and weekly follow-up with food diaries.

We also introduced the concept of regular exercise, something she abhorred. With a lot of encouragement over several visits, we were able to get her to sign up for a package of ten sessions with a trainer at a local gym. She began to see positive changes in her body, which reinforced this activity.

I started her on a cyclic oral contraceptive pill with 35 micrograms of ethinyl estradiol. As a young non-smoker, this higher dose afforded her the greatest potential positive impact on her SHBG and free testosterone. Her period returned to a more regular monthly flow.

We added to her regimen a supplement containing saw palmetto, stinging nettle root, and pygeum to reduce conversion of testosterone to dihydrotestosterone and reduce her androgenic symptoms. I also placed her on berberine and quercetin to improve her insulin sensitivity and aid in weight loss and improved ovulation. She enlisted a local laser therapist for her excess hair growth.

After a year, Melissa presented as a much happier young woman achieving her health goals. She lost over 25 pounds lowering her BMI to 24. Her skin was clear for the first time since childhood. After about six months, she began to see increased crown hair growth and had good response with several laser therapies to the affected areas. She was gratified to see regular monthly menses for the first time in years, voicing that she “finally felt normal.”

She enjoyed her newly discovered love of exercise and made several friends at the gym which reinforced her attendance. She was very attentive to her diet, educating her friends to pass over the pizza in favor of lean protein and steamed vegetables.

Her lab studies showed an increase in SHBG to the mid 80s. Her free and total testosterone had normalized. She is happy with her birth control pill as this has provided her with desired contraception while also helping to reduce her PCOS symptoms. We have discussed that when she is ready to conceive, we may need more aggressive therapy to aid in helping her achieve regular ovulation, but this is not currently a concern. Melissa continues to meet with me and the nutritionist regularly where we encourage and support her in her achievements.

References 

American College of Obstetricians and Gynecologists (2018). Polycystic Ovary Syndrome. Practice Bulletin Number 194.

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