Reproductive Conditions Associated with Infertility and Infertility Treatment

Reproductive disorders are very common.

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In fact, hormonal disorders are the third most diagnosed condition in the United States, and infertility affects roughly 1 in 6 couples. This is important because our reproductive wellness affects our overall health, and infertility is often the first sign of an underlying health condition. For these reasons, early detection of reproductive disorders is vital for preventing chronic issues. One of our most important missions at Pelex is focusing on early detection of reproductive disorders.

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Research has shown that infertility is associated with early death in both men and women. In fact, one study followed over 100,000 women from 25-42 years of age and found that infertility was associated with an increased risk for premature death, particularly due to cancer. This risk was higher in women with infertility at a younger age or for those who were never able to conceive, and the highest risk was associated with diagnoses of ovulatory disorders and endometriosis. Male infertility is also associated with morbidity and mortality, including the risks of cancer, as well as cardiovascular, metabolic, and autoimmune diseases. These associations may arise from a genetic predisposition, developmental  influences, or lifestyle-based origin, but the exact nature remains unclear. Research has found that semen quality may be a fundamental biomarker of a male’s overall health.

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If women have irregular menstrual cycles, they could have a wide range of underlying issues. For this reason, it is important for women to know when their last menstrual cycle began and if their menstrual cycles are occurring regularly. In a sense, the menstrual cycle should be considered the sixth vital sign. A common example of these underlying issues is polycystic ovary syndrome, or PCOS.

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Polycystic Ovary Syndrome (PCOS)

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PCOS is diagnosed if at least two of the following are present:

1. Irregular, infrequent, or prolonged menstrual cycles/periods
2. Excess androgen (male hormone) levels, which could present as facial/body hair formation (hirsutism), acne, and/or male-pattern baldness (though some women have no physical signs)
3. Polycystic ovaries (enlarged ovaries with many small follicles)

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Excess levels of androgens can increase the free testosterone levels in your blood. This can cause a few events to occur:

1. The pituitary gland releases more reproductive hormones. For example, excess LH production impacts the ovary and causes it to make more testosterone.
2. The testosterone causes the peripheral tissue to become insulin resistant. As a result, the body is forced to make more insulin (hyperinsulinemia). Increased insulin levels harden the ovaries, which can cause anovulation to occur, and also affect the liver, causing it to make less sex hormone binding globulins (SHBGs). SHBGs soak up testosterone in blood, so if there are less, there is more testosterone in the body. One way to help treat PCOS is to help create more SHBGs.

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The main focus for treating PCOS is improving insulin resistance. This can be done by:

1. Using a low glycemic (sugar) diet and/or intermittent fasting to decrease insulin spikes throughout the day (which would disrupt the ovary and liver)
2. Exercising to help decrease the excess glucose in the body 
3. Weight loss (even just 5% of body weight) to increase the body’s ability to process insulin and glucose. In fact, many women who lose even 5% of body weight begin to have regular cycles.
4. Medications called GLP-1 agonists (such as Metformin) can help improve insulin resistance and may help reverse effects of hyperinsulinemia

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For the population of patients trying to conceive, there are a few options available:

1. Take medications, such as Clomid and Letrozole for 5 days at the beginning of the menstrual cycle. These medications trick the pituitary gland into thinking that the ovaries are not working properly, so more FSH and LH are released.
2. Administer trigger shot (hCG) to trigger ovulation to occur. hCG is actually the pregnancy hormone, but it structurally mimics the hormone LH and lasts longer than LH.
3. In some more severe cases, FSH can be administered. In these cases, there is a risk of over-ovulation, so it’s important to make sure that multiple follicles are not growing in response to the medications.

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For the population of patients not trying to conceive, the primary treatment option is birth control pills. These work to:

1. Prevent endometrial cancer in many situations
2. Lower androgen (testosterone) levels by increasing SHBG production in the liver
3. Reduce acne and hair growth
4. In some situations, other medications to reduce hair growth or acne may also be prescribed.

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For PCOS, early diagnosis and intervention are important for quality of life and well-being, yet 50% of women see 3+ health professionals prior to diagnosis. Further, for ⅓ of these women, it takes >2 years to receive a diagnosis, and only 16% of women were satisfied with the health information and educational materials that they received about their condition.

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Relative Energy Deficiency in Sports (RED-S)

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Women who play sports may be at risk for relative energy deficiency in sports (previously known as the female athlete triad syndrome). Common conditions associated with RED-S are:

1. Menstrual irregularities, which affect up to 24% of adolescents and up to 60% of adult female athletes.
2. Disordered eating (restrictive diets, skipping meals), which affect up to 20% of female athletes in high school and up to 25% of female athletes in college. Restricted caloric intake deprives the body of essential nutrients required for bone and muscle metabolism. Athletes should have 1500 mg/day of calcium and 1500-2000 IU/day of vitamin D to maintain blood levels above 32-50.
3. Decreased bone density (in spite of the bone building effect of weight-bearing exercise). This can ultimately result in recurrent stress fractures, which are seen in up to 30% of ballet dancers and 32% of runners. Stress fractures are overuse injuries caused by repetitive stress (increased load and/or repetition, such as runners or gymnasts). The most significant risk factor for recurrent fractures is a history of stress fractures. Unfortunately, recurrent stress fractures can be career-ending for competitive athletes.

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Estrogen is the link between stress fractures and energy deficiency

• Estrogen stimulates the activity of osteoblasts (cells that produce bone) and inhibits the activity of osteoclasts (cells that resorb and weaken bone)
• A lack of estrogen causes osteoblasts to not effectively produce bone, and osteoclasts to further weaken bone and decrease bone density

• This leads to an increased risk of stress fractures

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Birth control: the Imposter

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Many women are put on birth control pills in their teens. While taking birth control, a monthly placebo week can cause vaginal withdrawal bleeding to occur, which many women mistake for a period. This can create a false reassurance of regular periods when there is actually an underlying issue present. Birth control pills provide steady levels of estrogen and progesterone each month, but this is different from the fluctuations observed in a normal menstrual cycle. Since the estrogen levels remain low, it can cause sustained or worsening fracture risks.

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Reproductive endocrinology can help with RED-S

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Reproductive endocrinology is important because it:

1. Prevents RED-S and possible injury through an initial workup (which provides a baseline for hormone levels and bone health) and serial monitoring.
2. Can help reverse and improve energy and hormone imbalances if RED-S is diagnosed.

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The ultimate goal is to optimize overall health and performance of the female athlete to prevent initial or recurrent injury.

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Menopause

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Menopause refers to the absence of a period for one year, so it takes one year to diagnose it.  Menopause can be treated with hormonal therapy. Women only taking estrogen had less breast and colorectal cancer, while women taking both estrogen and progesterone had lower all-cause mortality rates.

Pelex believes in preventative care for reproductive health

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Sadly, infertility and reproductive disorders are one of the only areas of medicine where prevention isn’t standard of care. At Pelex, we believe that:

1. Prevention of infertility is more important than just reacting to it
2. Couples should not be told to fail to conceive for 12 months before simple and inexpensive screening tests are allowed. Unfortunately, medical society guidelines actively dissuade couples from reproductive endocrinology and infertility care until they have failed to become pregnant for 6-12 months. This serves to funnel towards expensive treatments.
3. Reproductive screening for common conditions (e.g. PCOS, POI, endometriosis, and infertility) should be routine. For example, annual ovarian reserve blood tests (AMH) should be performed on all women. These changes would allow us to be proactive instead of reactive and can allow for early intervention and optimization of fertility.
4. The average couple should not wait 2-3 years to see a fertility specialist. After all, success rates of fertility treatments decline with age, while costs increase with delays because more treatment cycles are needed.

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Most importantly, reproductive wellness is important for overall health, even if you are not trying to conceive. Optimizing health early prevents costly treatment later on, so it’s important to screen for, diagnose, and treat reproductive and endocrine conditions early to improve overall health and decrease overall healthcare spending. This also prevents the need for time-intensive and costly treatments down the road.

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Patient examples

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1. A 31 year old female who started birth control pills at 20 to regulate her menstrual cycles and help with acne comes to Pelex. She receives regular care from her general practitioner, which includes annual pap smears and birth control pill refills. Although she meets the clinical criteria for PCOS (irregular menstrual cycles and acne), this has not been addressed by her providers.

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We know that women with PCOS are at a higher risk for pregnancy complications (e.g. miscarriage, gestational diabetes, pregnancy-induced hypertension, preeclampsia, and preterm birth). We also know that PCOS is associated with other comorbidities, including obesity, pre-diabetes/diabetes, metabolism syndrome (hypertension, high cholesterol, obesity), anxiety and depression, fatty liver disease, and obstructive sleep apnea.

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We counseled the patient to do the following:

1. Lose 5% of body weight to improve insulin sensitivity and decrease PCOS severity
2. Use a CPAP for sleep apnea
3. Start a medication to control blood sugar for prediabetes
4. Make a list of reproductive plans (the patient wants to have children in 2 years)
5. At a future checkup, we can discuss stopping her birth control pills to observe if she has regular periods. If she does not, we can prescribe her pills to help her ovulate
6. Make lifestyle changes now to reduce risk for cancer, cardiac conditions, and stroke later in life

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At her next appointment, the patient reported:

1. A decrease in body weight, which allowed her to begin exercising more
2. Significant energy improvement with the help of the CPAP
3. A decrease in her A1C levels from the prediabetes medication

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2. A 34 year old woman struggling to get pregnant for the past 14 months comes to Pelex for treatment. Her Pelex doctor ordered blood tests and diagnostic imaging. The results indicated that she has an underactive thyroid, which is causing luteal phase insufficiency.

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Luteal phase insufficiency is a hormonal imbalance that can be a result of thyroid or prolactin abnormalities, being overweight or underweight, excessive exercise, or experiencing excessive stress. It makes embryo implantation difficult because the period controls too early.

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We prescribed the patient oral medications to help with her thyroid function and ovulation, along with timed intercourse. As a result, the patient successfully became pregnant and was able to avoid expensive and invasive treatment such as IVF.

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3. A 49 year old woman struggling with poor sleep, anxiety, hot flashes, night sweats, brain fog, and joint pain comes to Pelex for treatment. We prescribed her a bioidentical, transdermal, low-dose estrogen patch with cyclic biochemical progesterone. The patch is important because it allows the hormones to not get absorbed by liver before they enter the rest of the body.

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Our plan is to start with a very low dose and gradually increase her dosage to optimal level. Pelex meets with patient 3 times to gradually titrate the dose to the lowest dose possible that is effective for the patient, which resolves her symptoms and quality of life.

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4. A 22 year old woman, who has not had a period for a year, recently noticed worsening energy and endurance at her exercise class. Her PelexSports provider orders blood work and a bone density scan at a local testing center. The results reveal low:

1. Pituitary hormone levels (FSH/LH)

2. Estrogen levels

3. Bone density for her age

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As a result, the patient meets with a Pelex Sports Dietician, who helps her with a weekly meal plan with adequate calories that will meet her energy requirements. A few months later, the patient reports that her energy has improved and her period has returned. A follow up scan shows improvement in her bone mineral density.

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Questions

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1. My friend has PCOS and did laser hair removal for facial hair, but it still continues to grow. Is there any way to help with her hair growth?

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Dr. Wolff: I would encourage your friend to start a birth control pill in order to control the levels of androgens in her system. That way, she will not need to continue doing the laser hair removal as often. New diabetic drugs are also revolutionizing how we treat PCOS because it helps correct a lot of molecular aspects associated with PCOS. This, in turn, can help prevent the hair growth and other physical characteristics associated with PCOS.

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2. Do other types of birth control (aside from the pills) show the same effects as the pills when it comes to PCOS?

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Dr. Wolff: An IUD, implants, or injections usually only contain progesterone, which can decrease endometrial hyperplasia and the endometrial cancer risk. However, if they do not include an estrogen component, then your body will not raise the sex hormone binding globulins (SHBGs), which can cause an increased level of androgens (testosterone) in the body. Options such as a patch or Nuvaring would help improve PCOS.

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3. What testing is done after two miscarriages?

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Dr. Wolff: We do a recurrent pregnancy loss workup, which includes any or all of the following:

1. A karyotype (of the sperm and egg source) to see if either has any genetic abnormalities. These can cause genetic abnormalities in embryos, which can cause them to not be viable.
2. A test of the mother/carrier’s thyroid and prolactin levels. Abnormalities in these levels can increase the risk of miscarriage.
3. A check of the uterine cavity for abnormalities, such as a septum. During fetal development, the uterus begins as two tubes that fuse together. When fusion occurs, the line in between them should be resorbed. In some cases, this line is not properly resorbed, which causes a line (septum) to remain in the middle of the uterus. This can be detected through an HSG or ultrasound and can sometimes be cut out or corrected. If an embryo implants on the septum, it will not receive the blood supply that it needs because the septum is fibrous and all of the uterus’s blood supply is located on the outer walls of the uterus.
4. Test for conditions such as antiphospholipid syndrome or hypercoagulable disorders. These are more commonly associated with second or third trimester losses. Some examples include autoimmune conditions or prothrombin mutations that are associated with hypercoagulability. 

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Rarely, recurrent miscarriage can be due to recurrent aneuploidy. As we get older, we have a higher chance of having a pregnancy where the chromosomes have abnormalities. In some cases, even younger patients have genetically abnormal embryos. For these patients, we recommend doing IVF and testing the embryos through preimplantation genetic testing (PGT). This can help determine which embryos have the correct number of chromosomes, which can increase the risk of a successful pregnancy. This is a popular option because the most common cause of miscarriages is having an embryo that has genetic abnormalities.

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4. Can you talk about the blood test that measures fertility?

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Dr. Wolff: With our basic labs, we do two things: we look at ovarian reserve markers (how many eggs are left in the ovaries) and screen for other things that can be causing infertility. The ovarian reserve markers include:

1. FSH levels (blood test): if these levels are too high, it can indicate that you have a lower number of eggs.
2. AMH (anti-Mullerian hormone, a blood test): this hormone is secreted by the ovaries. It can be either too high (which is usually indicative of PCOS) or too low (which is usually indicative of a diminished ovarian reserve, or a low egg number). 
3. Antral follicle count (ultrasound examination): this exam measures the number of follicles in the ovaries. The more antral follicles, the better your chances are of success. This can also help estimate how many eggs will be retrieved if you do IVF.

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5. What are your thoughts on following a plant-based or vegan diet on your overall health?

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Dr. Wolff: It depends on if your lifestyle allows you to maintain your health. If you have normal menstrual cycles and no other red flags, then you are likely getting an adequate amount of nutrients. Sometimes, though, women restrict their diets as a control mechanism to decrease their stress levels. In these cases, it becomes increasingly restrictive (disordered eating) and can affect your overall health. 

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6. How do you balance the use of Metformin and weight gain?

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Dr. Wolff: We used to use Metformin to induce ovulation and used it interchangeably with Clomid or Letrozole. A big study found that using Metformin by itself was not as effective as using Clomid, and using Clomid with Metformin is the same as using Clomid alone.

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With PCOS, there are subpopulations. When patients with PCOS have insulin resistance, I like to use Metformin. Metformin can cause nausea, stomach upset, and diarrhea, which can cause weight loss, so it also helps to kickstart weight loss so you can change your diet.

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7. Is it advisable for women with PCOS to take lime, lemon, and other citrus fruits? Do they impact your ability to conceive?

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Dr. Wolff: I don’t know of any association between citrus fruits and PCOS and fertility.

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8. Even if a woman is not sexually active, is it advisable that she takes birth control pills to avoid uterine fibroids?

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Dr. Wolff: Birth control pills can help a little bit with fibroids because they lower your levels of FSH and LH, which can decrease the rate of fibroid growth. But birth control pills are not usually very effective at treating fibroids.

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9. What is the current research showing about the age limit for natural pregnancy?

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Dr. Wolff: Our chances of getting pregnant naturally decrease after 35 years of age. It’s rare for patients to get pregnant on their own after around age 42, and menopause begins around 51 years of age. There are some circumstances when women get pregnant on their own in the mid to late 40s if there is still ovarian activity occurring, but it is rare.  

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10. Can you speak to any long-term health effects for IVF?

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Dr. Wolff: If you look at trends for patients that do IVF, they are at higher risks for pregnancy complications. However, these women are part of an infertile population. Really careful studies have found that infertile women who do IVF have the same risks as infertile women who do not do IVF. So, it is not the IVF that is causing these risks to the mother, but rather the infertility. Infertility is associated with ovarian cancer, endometriosis, PCOS, POI, and other reproductive conditions can cause worse outcomes later in life. 

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11. How do you diagnose endometriosis outside of surgery?

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Dr. Wolff: As a field, we have agreed to prescribe patients with suspected endometriosis a medication that induces a medical menopause, and then see how their bodies react. This medication turns off reproductive hormone function in your body to stop the stimulation of endometriosis. If you feel less pain or discomfort, we know the medication is working. This is a presumptive diagnosis.

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Outside of that, it’s usually indicative when a patient says that she has heavy, very painful periods and pain with deep penetration during intercourse. These symptoms are highly specific for endometriosis. The most definitive way is to get a sample of the tissue and test it.

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An ultrasound can also diagnose higher endometriosis. An endometrioma (chocolate cyst) on the ovary that is full of dark blood can give your provider a definitive diagnosis of endometriosis. 

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12. Is there anything that can be done to mitigate the mood changes for women with PCOS that take birth control?

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Dr. Wolff: Unfortunately, it’s more of a trial and error process. If one type of birth control does not seem to work, another class of birth control can be tried until one is found that minimizes that side effect.

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13. What are the pros and cons of egg freezing?

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Dr. Wolff: The most important pro is that it acts as an insurance policy if you need the eggs in the future. The younger you are when you freeze your eggs, the more likely it is that they will be genetically normal, which can increase your chances of a healthy pregnancy if they are utilized in the future. Further, up to ⅓ of all couples with infertility have male factor infertility, so you and your partner may require more eggs in order to achieve fertilization.

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The biggest con is the cost. Egg freezing is rarely covered by insurance and is quite expensive. Another con is that you can go through the process of freezing your eggs and may end up not needing them in the future.

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14. How should men with male factor infertility prepare for IVF?

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Dr. Wolff: To prepare, try to improve your overall health (decrease obesity, treat sleep apnea, moderate alcohol intake, stop marijuana use, etc.). You can also ask your PCP to test your testosterone levels or check for varicoceles, which may be impacting sperm quality. I also recommend having a semen analysis performed to determine if there is any male factor infertility.

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15. How soon before getting pregnant should one begin to take prenatal vitamins?

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Dr. Wolff: It depends on your folate levels since folate deficiencies can cause neural tube defects such as spina bifida in babies. But it’s generally advised to start at least 3 months prior to trying to conceive. But do not double your normal vitamins since some vitamins, such as vitamin A, can be toxic in high levels for pregnancy.

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16. How can I start the process with Pelex?

Dr. Wolff: You can book directly online (www.pelexmed.com) using our scheduling tool, or you can call us at 703-215-2467. You can also email us as info@pelexmed.com.