Question 26. If I don’t have either PCOS or POF, then what is my problem and why am I not ovulating?

Some patients really do stick in your mind long after they have left the practice. A couple of years ago we had a patient who had absent periods and had failed to respond to clomid or gonadotropin injections. She had been told by another RE that she needed donor egg and there was no reason to think that she would ever respond to fertility drugs. Now it is pretty uncommon to find yourself in the position of talking a patient out of donor egg IVF...but that is exactly what Dr D had to do. The patient consented to a final go at fertility drugs. But as she had FHA (see below) the stimulation was long with slow increases in drug dose. Ultimately she did respond and ended up with a great pregnancy with her own eggs. The key was to realize that the patient had FHA and not PCOS and use the correct recipe. It is all about cooking those follicles/eggs correctly....bad recipe = bad eggs.

So here is today's Question of the Day from the new and improved 2nd Edition of 100 Questions and Answers about Infertility.


26. If I don’t have either PCOS or POF, then what is my problem and why am I not ovulating?


Hormone abnormalities other than PCOS can also lead to irregular menstrual cycles. Such abnormalities include problems with the thyroid gland (which produces a hormone that controls metabolism), abnormal levels of prolactin (a hormone that induces breast milk production), and a lack of hypothalamic/pituitary stimulation to the ovary known as functional hypothalamic amenorrhea (FHA). The pituitary gland has been called the master gland of the body; it secretes hormones that control a wide range of functions, including reproduction, metabolism, response to stress, water balance, and growth.

Women with irregular cycles should have both their thyroid hormone and prolactin levels measured, as problems with the thyroid gland can indirectly lead to elevations in prolactin. Low levels of thyroid hormone (hypothyroidism) and elevations in prolactin (hyperprolactinemia) can be readily treated with medication. In fact, treatment of hypothyroidism with oral thyroid hormone (levothyroxine) can promptly restore normal menstruation. Similarly, hyperprolactinemia usually responds quickly to bromocriptine therapy, often promptly restoring normal cycles.

An elevation of prolactin in the absence of any thyroid disease requires magnetic resonance imaging (MRI) of the brain to evaluate its cause. In such cases, hyperprolactinemia usually results from an increased growth of the prolactin-secreting cells in the pituitary gland forming a small tumor. If the prolactin-secreting tumor is less than 1 cm in diameter, then it is called a microadenoma, whereas a macroadenoma is greater than 1 cm in diameter.

Women without thyroid or prolactin issues who fail to have menstrual periods following treatment with progesterone are usually referred to as having functional hypothalamic amenorrhea (FHA). These women fail to produce normal levels of estrogen despite an appropriate complement of ovarian follicles. Women who are below ideal body weight and who exercise frequently and vigorously are particularly prone to developing this problem. Women with FHA are at risk for osteoporosis and should discuss with their physician the benefits of hormone therapy (such as oral contraceptives) when not attempting pregnancy. They should also undergo an MRI of the brain to rule out any structural etiology for their condition. Women who are below ideal body weight may resume normal menstrual cycles when they gain weight or decrease their exercise frequency and duration.

Infertility in women with FHA can be readily treated with injectible gonadotropins. In such women, the choice of medication is important as the drug should contain both FSH and L (Menopur) and not just FSH alone (Gonal-F, Follistim). Clomid rarely works in women with FHA, but nearly all women with FHA can undergo successful ovulation induction. As was discussed in the preceding question, an excessive response may lead to high order multiple pregnancy so care should be taken to cancel such a cycle or convert it to IVF or consider a follicle reduction procedure.

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Question 25. I have PCOS and am still not having normal cycles with metformin. What comes next

PCOS is not at all an uncommon problem in our fertility practice. Although many OB GYN physicians advertise that they treat infertility, some really do not approach this common problem in a logical way. Instead, they give the patient a prescription for metformin or clomid and push the patient out the door. However, I still believe that having a logical plan is very important. My wife finds this hard to believe because according to her I am constantly flying by the seat of my pants. But that is my little secret and gets me off the hook for being responsible for many household chores....

So as we await the arrival of the heat and humidity here in Washington DC please take a minute to read this latest installment in my effort to keep up with the 2nd Edition of 100 Questions and Answers about Infertility.

25. I have PCOS and am still not having normal cycles with metformin. What comes next?


In our experience, most patients who will resume regular cycles on metformin will demonstrate regular cycles within 4 months of starting this medication. Patients who fail to respond to metformin may require ovulation induction with either clomiphene citrate (Clomid) or injectable fertility medications (gonadotropins).

Clomid has been an FDA-approved treatment for anovulation since the late 1960s. This anti-estrogen has been used successfully in millions of women with few complications. Clomid binds to estrogen receptors in the brain, causing the pituitary gland to resume normal release of FSH, and thereby inducing follicles to grow and ultimately release an egg. Patients should take the lowest effective dose of Clomid needed to induce ovulation. With increasing doses, the anti-estrogen side effects can reduce fertility by altering the cervical mucus and leading to a thinner endometrial lining. Many physicians initially prescribe a dose of 50 mg of Clomid to be taken on cycle days 5 to 9. The physician may perform ultrasound monitoring after day 12. Most patients will ovulate around day 17. If no dominant follicle emerges by this day, then an increased dose of 100 mg should be considered in the next cycle. A dose of 150 mg is rarely prescribed, because the vast majority of Clomid-responsive patients will ovulate while taking the 50- or 100-mg dose. Patients who ovulate rarely or not at all can be given medroxyprogesterone acetate (Provera) for 10 days to induce bleeding. By convention, the first day of this bleeding is referred to as cycle day #1 (eventhough it was an induced bleed and not the result of a normal cycle) and clomiphene is prescribed as noted above.

Women with PCOS who fail to respond to Clomid can be treated with injectable fertility hormones called gonadotropins. Such hormone medications are prepared either using recombinant DNA technology (Follistim, Gonal-F) or by isolating these hormones from the urine of postmenopausal women (Bravelle, Menopur). By following a very-low-dose protocol (37.5 IU as the starting dose), approximately 90% of patients will achieve a single dominant follicle. If the treatment produces multiple follicles, however, the woman’s risk of multiple pregnancy and ovarian hyperstimulation syndrome (OHSS) may lead to cycle cancellation. Alternatives to canceling the cycle and withholding HCG include conversion to IVF or performing a follicle aspiration procedure to reduce the number of follicles to a reasonable number but without fertilizing the eggs that were removed by the aspiration procedure. Almost all of the high-order multiple pregnancies (e.g., sextuplets) born today result from PCOS patients who took gonadotropins and demonstrated an excessive follicular response (think Jon and Kate Plus Eight).

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Question 24. If I have PCOS, why do I need to take metformin? Isn’t that a drug for diabetics?

I must admit that I am just running on fumes today. I was in Boston yesterday so that I could visit Mom and try to raise her spirits a bit. It is tough to get old but as my Grandmother always said "it beats the alternative." Unfortunately, her poor health over these past few months has prevented her from going on the internet and I hate to ask my Dad to download these posts as he tends to get very frustrated at times with the download/print/share sequence. That means that there are now only 3 people reading this blog....

So what does any of this have to do with infertility or PCOS? Nothing. Hey, I told you I was running on fumes. But seriously, after abandoning my Special K diet yesterday in exchange for the Sunday Brunch at the Wollaston Golf Club....I feel like I have become diabetic. Now diabetes is a topic that does have something to do with today's Question of the Day so please read on....

24. If I have PCOS, why do I need to take metformin? Isn’t that a drug for diabetics?

The role of insulin resistance as the probable initiating factor in PCOS has important clinical implications. Because of the pioneering work done by Drs. John Nestler and Andrea Dunaif, the treatment of patients with PCOS has now shifted toward addressing the underlying issue of insulin resistance. Patients with PCOS are often treated with an insulin-sensitizing medication such as metformin (Glucophage). More than 20% of patients with PCOS and irregular cycles will experience a restoration of their normal cycles with metformin treatment. Because most patients who take metformin experience a diminished appetite, they may also benefit from weight loss with this therapy. Patients with PCOS also have increased rates of first-trimester miscarriage, and preliminary data suggest that there is a reduced rate of miscarriage in patients with PCOS who are treated with metformin.

In order to minimize the gastrointestinal side effects, the dose of metformin is increased gradually. Many physicians initially prescribe 500 mg a day of the extended-release preparation of metformin, to be taken at dinner. After 1 week, the dose is increased to 1000 mg; after another week, the dose is increased to the maximum of 1500 mg. Most patients can tolerate the medication, although severe gastrointestinal side effects (mainly diarrhea) arise in 10% to 15% of patients. Patients who fail to resume predictable cycles with metformin therapy alone will need to consider ovulation induction with fertility medications.

The use of metformin as a first-line medication in the treatment of ovulation problems in patients with PCOS is controversial. Some physicians believe that clomiphene should be the first medication prescribed to women with PCOS who desire pregnancy and have irregular cycles. Our preference has been to start with metformin and then add clomiphene if a women fails to resume regular menstrual cycles.

Kristin comments:
My OB suggested I try metformin to regulate my cycles. I started on 500 mg and eventually went up to 1000 mg—and it worked. I started to get regular periods. By charting my basal body temperature, I could tell that I was ovulating. I experienced major gastrointestinal issues with the drug, but they subsided after a month or so with some flare-ups on occasion. The side effects were worth it as far as I was concerned, especially if the metformin was going to help me get pregnant. When I started seeing an RE, my metformin dose was upped to 1500 mg. Once I did get pregnant through IVF, I remained on metformin for the first trimester of my pregnancy.

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Question 23. What is polycystic ovarian syndrome? Where does it come from and how is it treated?

So after a weekend off I found myself completely swamped this morning. How 48 hours can make such a difference is beyond me. Following two egg I rushed out to Reston and then back again. Traffic was so bad this morning that I canceled my Monday morning lecture to the residents and medical students. Too bad for them because it was supposed to be on PCOS. This is the one topic in RE that they should fully understand because it is so common. Yet, week after week I get blank stares and incomplete answers to my questions. At first I though that they were bored but now I understand they are more confused than bored.

What they all need to do is to read 100 Questions and Answers about Infertility from cover to cover. Then they will be at least as smart as my patients.....

So Happy Monday and here is today's Question of the Day!


23. What is polycystic ovarian syndrome? Where does it come from and how is it treated?

Polycystic ovarian syndrome (PCOS) is an exceedingly common reproductive disorder, affecting an estimated 10% to 15% of reproductive-age women. The diagnosis of PCOS is a clinical one. In 2003, the ESHRE/ASRM consensus conference redefined PCOS as the presence of at least two out of the three following clinical criteria:


1. Irregular menstrual cycles
2. Evidence of extra male hormones, as determined either by clinical examination or by blood tests
3. Ultrasound demonstrating ovaries with numerous small follicles (PCO-appearing ovaries)

Previously, only patients with irregular menstrual cycles were thought to have PCOS, so the expansion of this definition has led to some confusion among healthcare providers. Other features commonly associated with PCOS include obesity, insulin resistance, borderline diabetes, skin tags, and a velvety discoloration on the nape of the neck and inner thighs called acanthosis nigricans. The topic of PCOS can fill an entire book. In fact, several books have been devoted to this subject. Although this condition was originally described by Drs. Stein and Leventhal in 1935, our understanding of PCOS has advanced significantly in the last decade.

Originally, PCOS was thought to be an anatomical problem in which a thickened coating around the ovary prevented ovulation. It is now agreed that PCOS represents a hormonal imbalance. At the heart of this disorder is insulin resistance. Insulin is a hormone secreted by the pancreas that induces your body to store the sugar circulating in the bloodstream. Individuals who fail to produce insulin as a result of an autoimmune disorder require insulin therapy to maintain normal blood sugar levels. These patients are referred to as having insulin-dependent diabetes (also known as type 1 diabetes).

The majority of patients with impaired glucose metabolism actually suffer from insulin resistance rather than insulin deficiency. That is, the cells of their bodies are not sensitive to the effects of insulin, so they require ever-increasing amounts of insulin to be released from the pancreas until appropriate blood levels of glucose are obtained. These patients are commonly referred to as having non-insulin-dependent diabetes (also known as type 2 diabetes or adult-onset diabetes). Despite the name of the disease, persons with type 2 diabetes may require insulin injections to maintain normal glucose levels depending on their degree of insulin resistance.

Insulin resistance is often a genetic disorder. This explains why adult-onset type 2 diabetes is so prevalent in certain families and in certain ethnic groups. In patients who are insulin resistant, the excessive levels of insulin affect not only their metabolism, but also their reproductive system. Insulin directly affects the release of reproductive hormones from the pituitary gland and directly stimulates ovarian production of male hormones. Thus the presence of excess insulin results in a local environment that is not conducive to follicle growth. The multiple follicles that fail to grow produce excessive male hormones, resulting in acne and abnormal hair growth commonly encountered in women with PCOS. Obesity itself also increases insulin resistance, so patients can find themselves trapped in a vicious cycle of irregular cycles and worsening weight gain. Women who have always had regular periods during their entire life but suddenly gain significant weight may frequently resemble patients with PCOS. In these cases, weight loss by itself may restore normal cycles and improve fertility.

Kristin comments:
Looking back at my early menstrual cycles, it should have come as no surprise that my reproductive system was not in normal working order. I had extremely heavy periods, but they were never regular. Sometimes I would go months without a period. I didn’t think much about it until my husband and I started trying to get pregnant. I went off the pill and got a period about 2 months later. I began charting my basal body temperature and discovered that I was not ovulating. I decided to be proactive and saw my OB, who confirmed that I have PCOS. This diagnosis was further confirmed at my first RE visit. The doctor did a transvaginal ultrasound, which showed that both of my ovaries were covered with many small follicles. I did meet the clinical criteria for diagnosing PCOS, but I did not exhibit any of the outwardly apparent features—obesity, skin tags, acanthosis nigricans.

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