The Basic Infertility Work-Up

After 1 year of unsuccessfully trying to have a baby, it is time to have a basic infertility evaluation. And the urgency increases the older the woman is.

A: Preparatory Tests done on the woman:

  • Tests for Ovarian Reserve: On the third day of spontaneous or progesterone withdrawal menstruation, blood is drawn to test for ovarian reserve. This requires testing for blood concentrations of estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH) and for anti-Mullerian hormone (AMH).
  • A hysterosalpingogram (HSG): This is performed within a week of the cessation of menstruation. This out-patient procedure involves injection of a radio-opaque dye which outlines the fallopian tubes allowing the diagnosis of tubal blockage. To a lesser degree, it permits the detection of surface lesions inside the uterine cavity.
  • Hysterosonogram (HSN) : When IVF is planned this procedure is done early in the menstrual cycle. It involves instilling a sterile saline solution into th uterus, followed by a pelvic ultrasound to map the contour of the uterine cavity.
  • Laparoscopy: This is a procedure that is sometimes needed. It is usually performed under general anesthesia in an ambulatory surgical center. Here, a telescope like instrument is passed into the abdominal cavity to allow thorough inspection of pelvic structures. It is usually confined to cases where symptoms and signs backed up by pelvic ultrasound findings, suggest significant underlying organic pelvic pathology (e.g. advanced endometriosis/fibroids, tubal disease and pelvic adhesions
  • Hysteroscopy: Women suspected on the basis of symptoms and/or signs, (usually following ultrasound assessment or HSN) of having intrauterine pathology (fibroids/polyps/scar tissue) that might interfere with embryo implantation are sometimes required to undergo a hysteroscopy. This involves introducing a thin telescope-like instrument via the vagina and cervix into the uterus in order to allow visualization of the uterine cavity and surgical repair. It can be performed under local anesthesia with sedation in an ambulatory center orin-office. In some cases general anesthesia is needed.
  • Testing the urine LH surge…for impending ovulation: Commencing at least 17 days before the expected menstrual period (i.e.; usually about 10 days following the initiation of menstruation), urine should be collected twice daily and tested for the onset of the spontaneous luteinizing hormone (LH) surge. The initiation of the LH surge usually precedes ovulation by 8 to 36 hours. In order to detect the onset of the LH surge accurately, an early morning urine specimen is needed. Ideally, the bladder should be emptied first thing in the morning, upon awakening. About one half-hour later urine is collected (only a very small amount is required) and tested using an over-the-counter LH – kit (obtainable over the counter, at a drug store). At the earliest sign of a color change the woman should present at her treating physician’s office for:

The 1st In-Office Assessment where the following is carried out::

      1. A pelvic ultrasound examination to assess for a dominant follicle or for evidence of recent ovulation and for the thickness and pattern of her uterine lining to be assessed (ideally it should measure >8mm with a triple “line” (trilaminar) appearance
      2. Blood should be tested for measurement of estradiol (E2) l level.

A 2nd  In-Office Assessment is arranged for three (3) days after the first office assessment. At this visit, a vaginal ultrasound exam is performed to check (or to confirm) that ovulation has occurred (i.e. whether the egg has been released). The presence of small amount of fluid collecting in the lowermost region of the pelvis, or a change in the shape of the follicle is suggestive of ovulation.

A 3rd In-Office Assessment takes place five (5) days after the 2nd visit.  At this visit, blood is drawn for the measurement of progesterone (P4) and estradiol (E2)

  • Assessment for an Immunologic Implantation Dysfunction (IID) This is selectively done at one of about six Reproductive Immunology Reference Laboratories in the United States (I preferentially use Reproductive Immunology Associates [RIA] in Van Nuys, CA). Testing is indicated when:
    1. Autoimmune assessment; In my opinion, this is indicated when here is a personal or family history of autoimmune diseases (e.g. Lupus Erythematosus, Hypothyroidism, Rheumatoid Arthritis etc.), symptoms or signs of endometriosis (e.g. prior surgical visualization of lesions in the pelvis, heavy painful periods and pain during intercourse and/or ovulation) which is associated with immunologic implantation dysfunction (IID) in about 1/3 of cases. Also, when there is a past history of repeated “unexplained” IVF failure. Here, blood is drawn (at any time) from the female partner and sent to a reliable Reproductive Immunology Reference Laboratory for testing of antiphospholipid antibodies (APA), antithyroid antibodies (ATA) and the K-562 Target cell test, otherwise known as a natural killer cell activity test (NKa) test. In some cases, a uterine biopsy is done to test for endometrial cytokines.
    2. Alloimmune assessment: In select cases (especially where there is a history of Recurrent Pregnancy Loss (RPL), or “unexplained” secondary infertility or where Natural Killer cell activation (NKa) is diagnosed without there being an underlying autoimmune cause, both partners should be tested for alloimmune genetic similarities (DQ alpha and HLA genetic matching).
  • A semen analysis is required for accurate measurement of sperm motility and count.  Sperm morphology is assessed employing “strict (Kruger) criteria.”
  • Sperm Antibody Test: Selectively we also test the man and/or the woman’s blood for anti-sperm antibodies (ASA) using the indirect Immunobead test (IBT). This is particularly important in cases of “unexplained” infertility (where the blood of both partners should ideally be tested) in men when there is a history of a prior vasectomy or sperm microscopy reveals significant sperm-to-sperm attachment (agglutination).
  • Sperm Chromatin Structure Assay (SCSA): In selected cases, semen should also be sent for a Sperm Chromatin Structure Assay (SCSA) to assess the DNA Fragmentation Index (DFI) which ideally should be <15%, but 15%-30%
  • Hormonal assessment of the man: in an ambulatory surgical center, performed In men where a semen analysis reveals a low count/motility/morphology, blood id collected from the man for FSH, LH, TSH, testosterone and prolactin measurement
  • Male Urology Visit: In selected cases (the man is referred to an Urologist for further testing or testicular biopsy.

6 Comments

Bethel eghe

Good morning sir. Pls I need ur phone number. Cos I have no child to call my own now. So how can I meet u one on one

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Dr. Geoffrey Sher

Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
Julie Dahan
• Email: Julied@sherivf.com
• Phone: 702-533-2691
 800-780-7437

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Katie Skinner

Is a DQ alpha test and HLA genetic matching test the same thing or is this 2 different tests? We have had an HLA test done and been told that we have a partial match. Should we be asking about a DQ Alpha test too? Thanks,

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Par

My first cycle I had 8 eggs, 5 fertilized, 2 reached to blastocyst stage on day 5. After genetic testing we had 1 that was low level mosaic.

On the second cycle I had 12 eggs, 8 fertilized and 1 reached to blastocyst stage on day 5 (3AB) the other 3BC on day 7. Neither were genetically tested.

What are the chances of a 3BC from day 7 resulting in a live birth? I imagine very low especially when it hasn’t been genetically tested . Also which is more likely to lead to a live birth, the low level mosaic or the embryo from day 7?

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Dr. Geoffrey Sher

In my opinion, embryos that do not reach blastocyst by day 6 are highly unlikely to propagate a viavle pregnancy.

So Sorry!

I think we should talk because it is very possible that the protocol used for ovarian stimulation could be at the root of tyhe problem.

The importance of the IVF stimulation protocol on egg/embryo quality cannot be overstated. This factor seems often to be overlooked or discounted by t IVF practitioners who use a “one-size-fits-all” approach to ovarian stimulation. My experience is that the use of individualized/customized COS protocols can greatly improve IVF outcome. While no one can influence underlying genetics or turn back the clock on a woman’s age, any competent IVF specialist should be able to tailor the protocol for COS to meet the individual needs of the patient.
Gonadotropins (LH and FSH), whether produced by the pituitary gland or administered by way of fertility drugs, have different “targeted” sites of action in the ovary. FSH targets cells that line the inner wall of the follicle (granulosa cells) and also form the cumulus cells that bind the egg to the inner surface of the follicle. Granulosa cells are responsible for estrogen production.
LH, on the other hand, targets the ovarian connective tissue (stroma/theca) that surrounds ovarian follicles resulting in the production of male hormones such as testosterone (predominantly), androstenedione and DHEA. These androgens are then transported to the granulosa cells of the adjacent follicles in a “bucket brigade fashion”. There FSH converts testosterone to estradiol, causing granulosa cells to multiply (proliferate) and produce estradiol, follicles to grows and eggs to develop (ovogenesis) It follows that ovarian androgens (mainly testosterone) is absolutely indispensable to follicle/ egg growth and development.
However, the emphasis is on a “normal” amount of testosterone. Over-exposure of the follicle to testosterone can in my opinion, compromise egg development and lead to an increased likelihood of chromosomal irregularities (aneuploid) following LH/hCG-induced egg maturational division (meiosis) and compromise embryo “competency/quality.
Ovarian androgens can also reach the uterine lining where they sometimes will compromise estrogen receptor -induced endometrial growth and development.
A significant percentage of older women and those who have diminished ovarian reserve (DOR) have increased LH activity is increased. Such women either over-produce LH and/or the LH produced is far more biologically active. Chronically increased LH activity leads to overgrowth of ovarian connective tissue (stroma/theca). This condition, which is often referred to as Stromal Hyperplasia or hyperthecosis can result in excessive ovarian androgen/testosterone production and poorer egg-embryo quality/competency, Similarly, women with polycystic ovarian syndrome (PCOS), also characteristically have Stromal hyperplasia/hyperthecosis due to chronically increased LH activity. Thus they too often manifest with increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often also a feature of PCOS.
In my opinion, the over-administration of LH-containing menotropins such as Menopur, [which is comprised of roughly equal amount of FSH and hCG ,which acts similar to LH)], to older women, women with DOR and those who have PCOS can also lead to reduced egg/embryo competency . Similarly, drugs such as clomiphene or Letrozole that cause the pituitary gland to release excessive amounts of LH, are also potentially harmful to egg development and in my opinion, are best omitted from IVF COS protocols. This is especially the case when it comes to older women and those with DOR, who in my opinion should preferably be stimulated using FSH-dominant products such as Follistim, Puregon, Fostimon and Gonal-F.
Gonadotropin releasing hormone agonists (GnRHa): GnRHa such as Lupron, Buserelin, Superfact, Gonopeptyl etc. are often used to launch ovarian stimulation cycles. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in LH levels falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. When GnRHa are administered for about 7 days prior to initiating gonadotropin stimulation (“long” pituitary down-regulation”), the LH depletion that will exist when COS is initiated, will usually be protective of subsequent egg development. In contrast, when the GnRHa administration commences along with the initiation of gonadotropin therapy, there will be a resultant immediate surge in the release of pituitary LH with the potential to increase ovarian testosterone to egg-compromising levels , from the outset of COS. This, in my opinion could be particularly harmful when undertaken in older women and those who have DOR.
GnRH-antagonists such as Ganirelix, Cetrotide and Orgalutron, on the other hand, act very rapidly (within hours) to block pituitary LH release. The purpose in using GnRH antagonists is to prevent the release of LH during COS. In contrast, the LH-lowering effect of GnRH agonists develops over a number of days.
GnRH antagonists are traditionally given, starting after 5th -7th day of gonadotropin stimulation. However, when this is done in older women and those (regardless of age) who have DOR, LH-suppression might be reached too late to prevent the deleterious effect of excessive ovarian androgen production on egg development in the early stage of ovarian stimulation. This is why, it is my preference to administer GnRH-antagonists, starting at the initiation of gonadotropin administration.
My preferred Protocols for Controlled Ovarian Stimulation (COS):
1. “Long” GnRHa (Lupron/Buserelin/Superfact/Gonopeptyl) Pituitary Down-regulation Protocol: The most commonly prescribed protocol for GnRHa/gonadotropin administration is the so-called “long protocol”. Here, GnRHa is given, starting a week or so prior to menstruation. This results in an initial rise in FSH and LH , which is rapidly followed by a precipitous fall to near zero. It is followed by a withdrawal bleed (menstruation), whereupon gonadotropin treatment should commence, while daily Lupron injections continue, to ensure a “low LH” environment. A modification to the “long protocol” which I prefer prescribing for older women and in cases of DOR, is the Agonist/Antagonist Conversion Protocol (A/ACP) where, upon the onset of a GnRHa-induced bleed, the agonist is supplanted by an antagonist (Ganirelix/Cetrotide/Orgalutron) and this is continued until the hCG trigger. In many such cases I often supplement with human growth hormone (HGH) in such cases in an attempt to enhance egg mitochondrial activity and so enhance egg development. This approach is often augmented with preimplantation genetic screening (PGS) of all embryos that reach the expanded blastocyst stage of development by day 5-6 post-fertilization. I also commonly recommend blastocyst banking to many such patients.
2. Short (“Flare”) GnRHa Protocol: Another GnRHa usage for COS is the so called “(micro) flare protocol”. This involves initiating gonadotropin therapy commensurate with initiation of gonadotropin administration. The supposed objective is to deliberately allow Lupron to elicit an initial surge (“flare”) in pituitary FSH release in order to augment FSH administration by increased FSH production. Unfortunately, this “spring board effect” constitutes “a double-edged sword”. While it indeed increases the release of FSH, it at the same time causes a surge in LH release. The latter can evoke excessive ovarian stromal/thecal androgen production which could potentially compromise egg quality, especially when it comes to older women and women with DOR. I am of the opinion that by evoking an exaggerated ovarian androgen response, such “(micro) flare protocols” can harm egg/embryo quality and reduce IVF success rates, especially when it comes to COS in older women, and in women with diminished ovarian reserve. Accordingly, I do not prescribe such protocols to my IVF patients.
3. Estrogen Priming – This is the approach I sometimes prescribe for my patients who have virtually depleted ovarian reserve , as determined by very low blood anti-Mullerian hormone AMH levels (<0.2ng/ml or 2 pmol/L) and are thus likely to be very “poor responders”. It involves a modified A/ACP. We start with estrogen skin patches applied every 2nd day (or with the BCP) for 10 days or longer, overlap it for 3 days with a GnRHa whereupon the estrogen priming is stopped. Th GnRHa is continued until the onset of menstruation (usually 5-7 days later) to cause pituitary LH, down-regulation. Upon menstruation and confirmation by ultrasound and measurement of blood estradiol levels that adequate ovarian suppression has been achieved, The patient is given twice-weekly injections of estradiol valerate (Delestrogen) for a period of 7-8 days whereupon COS is initiated using a relatively high dosage FSH-(Follistim, Fostimon, Puregon or Gonal F), which is continued along with daily administration of GnRH antagonist until the “hCG “trigger.” This approach is often augmented with HGH administration throughout the process of COS and by preimplantation genetic screening (PGS) of all embryos that reach the expanded blastocyst stage of development by day 5-6 post-fertilization. I also commonly recommend blastocyst banking to many such patients.
Estrogen Priming has succeeded in significantly enhancing ovarian response to gonadotropins in many of otherwise very poor responders.
Triggering egg Maturation prior to egg Retrieval: hCG versus GnRHa
With ovulation induction using fertility drugs, the administration of 10,000U hCGu (Pregnyl; Profasi, Novarel) or 500mcg hCGr (Ovidrel/Ovitrel) “trigger”) sends the eggs (into maturational division (meiosis). This process is designed to halve the chromosome number, resulting in mature eggs (M2) that will have 23 chromosomes rather that the 46 chromosomes they had prior to the “trigger”. Such a chromosomally numerically normal (euploid), mature (MII) eggs, upon being fertilized will (hopefully) propagate euploid embryos that have 46 chromosomes and will be “: competent” to propagate viable pregnancies. In my opinion, the key is to always “trigger” with no less than 10,000U of hCGu or 500mcg hCGr (Ovidrel/Ovitrel). Any lesser dosage often will reduce the efficiency of meiosis and increase the risk of the eggs being aneuploid. I personally do not use the agonist (Lupron) “trigger”, unless it is combined with (low dosage) hCG. The supposed reason for using the agonist, (Lupron) “trigger” is that by inducing meiosis through compelling a surge in the release of LH by the pituitary gland, the risk it reduces the risk of OHSS. This may be true, but it comes at the expense of egg quality because the extent of the induced LH surge varies and if too little LH is released, meiosis can be compromised, thereby increasing the likelihood of aneuploid and immature (MI) eggs. And there are other better approaches to preventing OHSS (e.g. “prolonged coasting”), in my opinion.
Use of the Birth Control Pill (BCP) to launch IVF-COS.
In natural (unstimulated) as well as in cycles stimulated with fertility drugs, the ability of follicles to properly respond to FSH stimulation is dependent on their having developed FSH-responsive receptors. Pre-antral follicles (PAF) do not have such primed FSH receptors and thus cannot respond properly to FSH stimulation with gonadotropins. The acquisition of FSH receptor responsivity requires that the pre-antral follicles be exposed to FSH, for a number of days (5-7) during which time they attain “FSH-responsivity” and are now known as antral follicles (AF). These AF’s are now able to respond properly to stimulation with administered FSH-gonadotropins. In regular menstrual cycles, the rising FSH output from the pituitary gland insures that PAFs convert tor AF’s. The BCP (as well as prolonged administration of estrogen/progesterone) suppresses FSH. This suppression needs to be countered by artificially causing blood FSH levels to rise in order to cause PAF to AF conversion prior to COS commencing, otherwise pre-antral-to –antral follicle conversion will not take place in an orderly fashion, the duration of ovarian stimulation will be prolonged and both follicle and egg development may be compromised. GnRH agonists cause an immediate surge in release of FSH by the pituitary gland thus causing conversion from PAF to SAF. This is why women who take a BCP to launch a cycle of COS need to have an overlap of the BCP with an agonist. By overlapping the BCP with an agonist for a few days prior to menstruation the early recruited follicles are able to complete their developmental drive to the AF stage and as such, be ready to respond appropriately to optimal ovarian stimulation. Using this approach, the timing of the initiation of the IVF treatment cycle can readily and safely be regulated and controlled by varying the length of time that the woman is on the BCP.
Since optimizing follicular response to COS requires that prior to stimulation with gonadotropins, FSH-induced conversion from PAF to AF’s first be completed and the BCP suppresses FSH, it follows when it comes to women launching COS coming off a BCP something needs to be done to cause a rise in FSH for 5-7 days prior to menstruation heralding the cycle of CO S. This is where overlapping the BCP with a GnRHa comes in. The agonist causes FSH to be released by the pituitary gland and if overlapped with the BCP for several days and this will (within 2-5 days) facilitate PAF to AF conversion…. in time to start COS with the onset of menstruation. Initiating ovarian stimulation in women taking a BCP, without doing this is suboptimal.
I strongly recommend that you visit www.SherIVF.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
• The Fundamental Requirements For Achieving Optimal IVF Success
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
• A Rational Basis for selecting Controlled Ovarian Stimulation (COS) protocols in women with Diminished Ovarian Reserve (DOR)
• Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
• Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
• Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
• Optimizing Response to Ovarian Stimulation in Women with Compromised Ovarian Response to Ovarian Stimulation: A Personal Approach.
• Egg Maturation in IVF: How Egg “Immaturity”, “Post-maturity” and “Dysmaturity” Influence IVF Outcome:
• Commonly Asked Question in IVF: “Why Did so Few of my Eggs Fertilize and, so Many Fail to Reach Blastocyst?”
• 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?
• Staggered IVF
• Staggered IVF with PGS- Selection of “Competent” Embryos Greatly Enhances the Utility & Efficiency of IVF.
• Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
• Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation
• Preimplantation Genetic Testing (PGS) in IVF: It should be Used Selectively and NOT be Routine.
• IVF: Selecting the Best Quality Embryos to Transfer
• Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
• PGS in IVF: Are Some Chromosomally abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
• PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
• IVF outcome: How Does Advancing Age and Diminished Ovarian Reserve (DOR) Affect Egg/Embryo “Competency” and How Should the Problem be addressed.

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ADDENDUM: PLEASE READ!!
INTRODUCING SHER FERTILITY SOLUTIONS (SFS)
Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.

If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or, enroll online on then home-page of my website (www.SherIVF.com).

PLEASE SPREAD THE WORD ABOUT SFS!

Geoff Sher

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