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The Causes of Infertility

by Dr. Geoffrey Sher on June 23, 2017

Neither sex contributes more heavily than the other to infertility problems. Roughly one‑third of all infertile couples can trace their infertility to the woman, one‑third to the man, and one‑third to both partners. In practice this means that in >50% of cases there is both a male and a female factor involved. Understanding this reality before embarking on a strategic plan of treatment is in my opinion essential to optimizing outcome.

Female infertility

  • Organic Pelvic Disease: The most common cause in a woman is damaged or blocked fallopian tubes that prevent the egg and sperm from uniting. Sexually transmitted diseases such as Chlamydia and Gonorrhea are a major cause of tubal scarring and blockage. In addition, scar tissue that forms after pelvic surgery may also lead to fertility problems. Conditions such as endometriosis, in which the lining of the uterus grows outside the womb (causing scarring, pain, and heavy bleeding), can also damage the fallopian tubes and ovaries. The presence of even a minimal amount of endometriosis in the pelvis is believed to adversely affect fertility by releasing toxic substances that might reduce the potential of the egg to be fertilized. The egg, of course, passes from the ovary through this environment to the fallopian tube, so while the presence of minimal endometriosis might not necessarily adversely affect the transportation mechanism, the exposure of eggs to this toxic environment diminishes its ability to become fertilized. It has also been shown that even the mildest form of endometriosis releases “toxins” into the local; pelvic environment. This can damage the woman’s eggs as they pass from the ovary(ies) with ovulation to the Fallopian tube(s) where the sperm are waiting. Once exposed to such “toxins” the envelopment of the egg (zona pellucida) becomes resistant to fertilization. This explains why all women with endometriosis (regardless of its severity) have markedly reduced fertility potential.
  • Anatomical Ovarian Disease: Damaged ovaries may also contribute to infertility. Diseases such as chronic pelvic inflammatory disease, pelvic tuberculosis (mainly seen in Asia and Africa) advanced endometriosis, as well as post-surgically scarring, can compromise blood flow to the ovaries or directly destroy egg bearing ovarian tissue. It can also anchor the ovaries to surrounding pelvic structures , binding them down in an awkward position or creating a barrier that prevents the finger like extremities of the fallopian tubes (fimbriae) from applying themselves properly to the ovaries’ surface, thereby compromising “pick up” the egg at the time of ovulation.
  • Ovulation dysfunction; One of the reasons that normal fertility usually wanes after 35 is because ovulation is more likely to become abnormal later in the childbearing years. Dysfunctional or absent ovulation is a frequent cause of female infertility. Some women do not ovulate at all, while others ovulate too early or too late in their cycle for a pregnancy to occur and survive. The older the woman and the closer she gets to menopause the greater the likelihood of hormonal dysfunction, irregular or absent ovulation. Such hormonal dysfunction can also occur independent of advancing age or proximity to menopause. Examples include hypothalamic anovulation, luteal and follicular phase insufficiency. Of course ovulation ceases with the onset of the menopause. It follow s that detection of irregular/absent menstruation or dysfunctional ovulation requires that ovarian reserve (AMH/FSH/LH/E2/) be tested and that future treatment be tailored accordingly.
  • Egg quality/”competency”: The “competency”/quality of eggs inevitably declines progressively as women age beyond the early 30’s. This is largely because the older the woman, the more compromised egg maturation (Meiosis/maturational division/) which takes place 36-42 hours prior to ovulation, becomes. As a result the percentage of eggs that are chromosomally normal declines from around 1: 2 (in the early thirties) to about 1: 20 by the time the woman reaches 45y of age. Such chromosomally irregular eggs (aneuploid) are less likely to fertilize, develop normally, implant successfully or propagate a viable pregnancy. This is why the older the woman becomes, the lower her fertility potential, the higher the risk of miscarriage and the greater the chance of birth defects due to numerical chromosomal irregularities (e.g. Down syndrome).
  • The uterine factor: A woman may also be infertile because disease, surgery, or infection has damaged the lining of her uterus. Damage caused by scarring or the presence of tumors, such as fibroids, may prevent the embryo from attaching to the endometrium and developing properly. Abnormalities in the size and shape of the uterus can also cause infertility problems. Sometimes women are born with an abnormally shaped uterus (congenital anomaly), but while this can cause mid-trimester miscarriages and premature birth, it rarely causes infertility. It is thus in my opinion inadvisable to remove a moderately severe uterine septum detected in the course or a routine assessment for infertility. Such practice can in my opinion lead to uterine scarring, and do more harm than good. Sometimes infertility is due to non-receptivity of the uterine lining (endometrium) to the embryo (fertilized and divided egg). This can be due be the lining being too thin to accommodate the implanting root system of the embryo, scarring of the lining, infection or immunologic factors. The latter is fast becoming an important consideration, especially in cases of unexplained failure following the use of fertility drugs.
  • The cervical mucus factor: Some women are unable to produce good quality estrogen-induced cervical mucus, required for vitalization of sperm passing through the cervical canal during natural conception. The production of hostile cervical mucus might be due to infection or due to anti-sperm antibodies or an allergic response to their partner’s sperm. Sperm antibodies may be passed into the cervical secretions and thereby prevent fertilization by destroying or immobilizing the sperm. Occasionally, surgery or injury to the cervix may have destroyed the glands that produce cervical secretions.
  • Immunologic Implantation Dysfunction: Some women develop antibodies to components of their own cells. This “autoimmune” process involves the production of antiphospholipid, antithyroid, and/or anti-ovarian antibodies – all of which may be associated with activation of Natural Killer (NK) cells in the uterine lining. Activated NK cells (NKa) release certain cytokines (TH-I) that if present in excess, often damage the trophoblast (the embryo’s root system) resulting in immunologic implantation dysfunction (IID). This can manifest as “infertility” or as early miscarriages). In other cases (though less common), the problem is due to “alloimmune” dysfunction. Here the genetic contribution by the male partner renders the embryo “too similar” to the mother. This in turn activates NK cells leading to implantation dysfunction. These IID’s are treated using combinations of medications such as heparin, Clexane, Lovenox, corticosteroids and intralipid (IL).

Male infertility

  • Hormonal dysfunction: As with women, abnormal central hypothalamic-pituitary regulation can lead to poor gamete production. There are many factors that play a role in normal testicular production but the predominant influence on testicular sperm and hormonal production is regulated by pituitary LH and FSH. FSH impacts spermatogenesis predominantly and LH, male hormone production. Pituitary LH and FSH production and release is under the influence of hypothalamic regulation. As in women, so also with men, numerous factors ranging from environmental and stress-related issues; drugs; hormonal supplementation (e.g. use of male hormones to treat low-testosterone effects in men), intracranial trauma and tumors and a variety of diseases, can influence regulation of LH and FSH production/release and so can influence male fertility profoundly. In other cases, testicular failure can affect sperm production directly. This can result from radiation; surgery; chemotherapy, etc. It can also result from undescended testes at birth. The testicles should have descended into the scrotum shortly after birth, but in some cases they do not reach the scrotum for years. In such circumstances it may be necessary to accomplish this surgically when the man is very young to prevent the testicles from becoming severely damaged, thereby resulting in infertility
  • Anatomical causes: The causes of male infertility are often more difficult to define. Blockage of the sperm ducts is one obvious cause. Generalized blockage may be caused by congenital absence of the sperm collecting ducts (vasa deferentia), from sexually transmitted diseases such as chlamydia or gonorrhea inflammation; trauma or from a prior vasectomy, done to effect male contraception.  While it is usually possible to surgically reconnect the tubes after vasectomy, some men, especially those who underwent the procedure more than 10 years earlier, remain infertile because in the interim their systems have developed an immune reaction that results in the production of antibodies that destroy or immobilize their own sperm. Another common anatomical cause of male infertility is a varicocele, a collection of dilated veins around the testicles that hinders sperm function by increasing body temperature in the scrotum. In order for the testicles to produce healthy sperm, the temperature in the scrotum must be lower than it is in the rest of the body.

Unexplained Infertility:

For about 10% of all infertile couples, the cause of the infertility cannot be readily determined by conventional diagnostic procedures. Such cases are referred to as “unexplained infertility.” Modern IVF technology is making great strides in helping to identify some of the causes of so called unexplained infertility. Improved testing techniques have made infertility easier to diagnose, and the majority of cases can now be diagnosed and generally are treatable. For example, recent research has demonstrated that many women with unexplained infertility ultimately are subsequently found to have pelvic endometriosis that cannot yet be detected by direct vision during laparoscopy or surgery. For example, a condition called non-pigmented endometriosis, in which the endometrium may be growing inside the pelvic cavity with many of the same deleterious effects as overt endometriosis, cannot be detected by direct vision because no visible bleeding has occurred in these lesions. The fertility of these patients may be every bit as much compromised by these conditions as if they had detectable endometriosis.  Sometimes infertility is due to non-receptivity of the uterine lining (endometrium) to the embryo (fertilized and divided egg). This can be due be the lining being too thin to accommodate the implanting root system of the embryo, scarring of the lining, infection or immunologic factors. The latter is fast becoming an important consideration, especially in cases of unexplained failure following the use of fertility drugs.

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  • Tej - June 25, 2017 reply

    Hello Doctor,
    I’m 31 years old and I had my IVF cycle 6 months back. 11 fertilized out of 13 matured eggs with ICSI and we transferred one 5AA embryo during the fresh cycle. It resulted in chemcal preg. with HCG value 32. We tried preparing for the FET cycle twice, but uterus didnt respond well with progynova. Triple line pattern had not been formed. So this time we are trying non medicated natural cycle and lining looked good.. about 9.1 mm on day12 with triple line. However, on doppler test the endometrium blood flow was recorded as zero. ( I believe zone3 blood flow). My RE says we can ignore it as they usually do not interpret the results for a natural cycle . Could you please give your opinion on this and will it effect my chances of pregnancy? Or is there anything I can do to improve the blood flow within next 4 days.
    Thanks much in advance.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - June 25, 2017 reply

    In my opinion, thickness of the endometrium is all that matters. About seventeen years ago, after reporting on the benefit of vaginal Sildenafil (Viagra) for to women who had implantation dysfunction due to thin endometrial linings I was proud to announce the birth of the world’s first “Viagra baby.” For those of you who aren’t familiar with the use of Viagra in IVF, allow me to provide some context.

    It was as far back as 1989, when I first published a study that examined the correlation between the thickness of a woman’s uterine lining (the endometrium), and the subsequent successful implantation of embryos in IVF patients. This study revealed that when the uterine lining measured <8mm in thickness by the day of the “hCG trigger” (in fresh IVF cycles), or at the time of initiating progesterone therapy (in embryo recipient cycles, e.g. frozen embryo transfers, egg donation-IVF etc.) , pregnancy and birth rates were substantially improved. Currently, it is my opinion, that an ideal estrogen-promoted endometrial lining should ideally measure at least 9mm in thickness and that an endometrial lining measuring 8-9mm is “intermediate”. An estrogenic lining of <8mm is in most cases unlikely to yield a viable pregnancy.

    A “poor” uterine lining is usually the result of the innermost layer of endometrium (the basal or germinal endometrium from which endometrium grows) ) not being able to respond to estrogen by propagating an outer, “functional” layer thick enough to support optimal embryo implantation and development of a healthy placenta (placentation). The “functional” layer ultimately comprises 2/3 of the full endometrial thickness and is the layer that sheds with menstruation in the event that no pregnancy occurs.

    The main causes of a “poor” uterine lining are:

    1. Damage to the basal endometrium as a result of:
    a. Inflammation of the endometrium (endometritis) most commonly resulting from infected products left over following abortion, miscarriage or birth
    b. Surgical trauma due to traumatic uterine scraping, (i.e. due to an over-aggressive D & C)
    2. Insensitivity of the basal endometrium to estrogen due to:
    a. Prolonged , over-use/misuse of clomiphene citrate
    b. Prenatal exposure to diethylstilbestrol (DES). This is a drug that was given to pregnant women in the 1960’s to help prevent miscarriage
    3. Over-exposure of the uterine lining to ovarian male hormones (mainly testosterone): Older women, women with diminished ovarian reserve (poor responders) and women with polycystic ovarian syndrome -PCOS tend to have raised LH biological activity.. This causes the connective tissue in the ovary (stroma/theca) to overproduce testosterone. The effect can be further exaggerated when certain methods for ovarian stimulation such as agonist (Lupron/Buserelin) “flare” protocols and high dosages of menotropins such as Menopur are used in such cases.
    4. Reduced blood flow to the basal endometrium:
    Examples include;
    a. Multiple uterine fibroids - especially when these are present under the endometrium (submucosal)
    b. Uterine adenomyosis (excessive, abnormal invasion of the uterine muscle by endometrial glands).

    “The Viagra Connection”

    Treatments such supplementary estrogen therapy, aspirin administration and/or administration of high dosage gonadotropin fertility drugs, aimed at improving endometrial development have all yielded disappointing results.

    It was in the 90’s that Sildenafil (brand named Viagra) was gaining popularity as a treatment for erectile dysfunction. The mechanism by which it acted was through increasing penile blood flow through increasing nitric oxide activity. This prompted me to investigate whether Viagra administered vaginally, might similarly improve uterine blood flow and in the process cause more estrogen to be delivered to the basal endometrium and thereby increase endometrial thickening. We found that when Viagra was administered vaginally it did just that! However oral administration was without any significant benefit in this regard. We enlisted the services of a compound pharmacy to produce vaginal Viagra suppositories. Initially, four (4) women with chronic histories of poor endometrial development and failure to conceive following several advanced fertility treatments were evaluated for a period of 4-6 weeks and then underwent IVF with concomitant Viagra therapy. Viagra suppositories were administered four times daily for 8-11 days and were discontinued 5-7 days prior to embryo transfer in all cases.

    Our findings clearly demonstrated that vaginal Viagra produced a rapid and profound improvement in uterine blood flow and that was followed by enhanced endometrial development in all four cases. Three (3) of the four women subsequently conceived. . I expanded the trial in 2002 and became the first to report on the administration of vaginal Viagra to 105 women with repeated IVF failure due to persistently thin endometrial linings. All of the women had experienced at least two (2) prior IVF failures attributed to intractably thin uterine linings. About 70% of these women responded to treatment with Viagra suppositories with a marked improvement in endometrial thickness. Forty five percent (45%) achieved live births following a single cycle of IVF treatment with Viagra The miscarriage rate was 9%. None of the women who had failed to show an improvement in endometrial thickness following Viagra treatment achieved viable pregnancies.
    Following vaginal administration, Viagra is rapidly absorbed and quickly reaches the uterine blood system in high concentrations. Thereupon it dilutes out as it is absorbed into the systemic circulation. This probably explains why treatment is virtually devoid of systemic side effects

    Since the introduction of this form of treatment, thousands of women with thin uterine linings have been reported treated and many have gone on to have babies after repeated prior IVF failure.

    It is important to recognize that Viagra will NOT be effective in improving endometrial thickness in all cases. In fact, about one third of women treated fail to show any improvement. This is because in certain cases of thin uterine linings, the basal endometrium will have been permanently damaged and left unresponsive to estrogen. This happens in cases of severe endometrial damage due mainly to post-pregnancy endometritis (inflammation), chronic granulomatous inflammation due to uterine tuberculosis (hardly ever seen in the United States) and following extensive surgical injury to the basal endometrium (as sometimes occurs following over-zealous D&C’s).

    To be effective, Viagra must be administered vaginally. It is NOT effective when taken orally. We prescribe 20mg vaginal suppositories to be inserted four times per day. Treatment is commenced soon after menstruation ceases and is continued until the day of the “hCG trigger.” While ideally the treatment should be sustained throughout the first half of the cycle, most women will respond within 48-72 hours. For this reason, Viagra can be used to “rescue” a poor lining after the cycle has already started, provided that there is enough time remaining prior to ovulation, egg retrieval or progesterone administration.


    Whenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
    It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
    1. Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
    2. Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
    We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about a decade ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
    3. The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.
    4. Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:
    a. A“ thin uterine lining”
    b. A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
    c. Immunologic implantation dysfunction (IID)
    d. Endocrine/molecular endometrial receptivity issues
    Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).
    I strongly recommend that you visit www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

    • The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • The Fundamental Requirements For Achieving Optimal IVF Success
    • Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
    • Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
    • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
    • Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
    • The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
    • Blastocyst Embryo Transfers Should be the Standard of Care in IVF
    • IVF: How Many Attempts should be considered before Stopping?
    • “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
    • IVF Failure and Implantation Dysfunction:
    • The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
    • Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
    • Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatment
    • Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
    • Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management:(Case Report
    • Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
    • Intralipid (IL) Administration in IVF: It’s Composition; How it Works; Administration; Side-effects; Reactions and Precautions
    • Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
    • Endometrial Thickness, Uterine Pathology and Immunologic Factors
    • Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
    • Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
    • A personalized, stepwise approach to IVF
    • How Many Embryos should be transferred: A Critical Decision in IVF.
    • The Role of Nutritional Supplements in Preparing for IVF
    1. About my Retirement
    After > 30 years in the field of Assisted Reproduction (AR), the time has finally come for me to contemplate retiring from full-time clinical medicine. If you are interested in my medical services prior to my retirement, I urge you to contact my concierge, Julie Dahan ASAP to set up a Skype or an in-person consultation with me. You can also contact Julie by phone or via email at 702-533-2691/ Julied@sherivf.com. You can also apply online at http://www.SherIVF.com.

    2. The 4th edition of my newest book ,
    “In Vitro Fertilization, the ART of Making Babies” is now available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

    Geoffrey Sher MD

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