I would need to consult directly with your daughters re ovarian stimulation. If you are interested, please reach outv to my assistant, Patti Converse (702-533-2691 ). Below is an article I wrote on Fragile-X FYI.

• Fragile X syndrome: Which IVF Candidates Should be Tested and How Should Results be Interpreted?

Fragile X syndrome occurs in individuals who carry the gene, FMR1 on an X-chromosome. This condition is inherited as a dominant X-linked disorder. With a dominant disorder, the condition results when there is only one copy of the altered gene in each cell.

Fragile syndrome occurs more  frequently in males (1:1,200) as compared to females (1:2,500) A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. The Fragile X gene, FMR1, can be passed on in a family by individuals who have no apparent signs of this genetic condition. In some families, a number of members appear to be affected, whereas in other families a newly diagnosed individual may be the first family member to exhibit symptoms.

By and large, Fragile X syndrome results from a mutation in the FMR1 gene where a segment, known (CGG triplet repeat), is expanded. Under normal circumstances, the CGG triplet is repeated from 5 to approximately 55 times. In contrast, those who have Fragile X syndrome will have more than 200 repeats. CGG segments prevent the FMR from propagating the formation of a specific protein needed to protect against the development of Fragile X syndrome. Thus over-expression of CGG triplet (>200 times) on an X chromosome represents a degree of loss of this “protective protein” as to lead to the development of fragile X syndrome. Since boys have only one X chromosome, Fragile X syndrome tends to manifest much more severely in males than in females, (who have two X chromosomes).

In a normal population, the number of repeated FMR1 genes varies from 5 to about 55. Those with 55 to 200 repeats of the CGG segment are said to have an FMR1 premutation (carriers”). In women, this is liable to increase to >200 repeats in the developing eggs. Accordingly, such women are at increased risk of having a child with fragile X syndrome. Conversely, when passed by men to the next generation, CGG repeats either remain the same in size or shorten. This is why men with a permutation do not transmit the disease. However they do transmit the permutation which if carried to a subsequent female offspring can result in them transmitting Fragile X syndrome in subsequent generations.

Both males and females with fragile X pre-mutation are by and large intellectually and physically normal in outward appearance. Some may manifest with mild but often socially harmful intellectual or behavioral symptoms,. They are however usually not infertile.

Some men with a premutation are at risk of developing a manifestation of fragile X-associated tremor/ataxia syndrome (FXTAS) a condition characterized by loss of balance, tremors and memory loss. It occurs in some older male carriers of the gene. Heart bone and skin problems are also often present. Age distribution is a s follows: Seventeen percent (17%) of males aged 50-59 years, in 38 percent of males aged 60-69 years, in 47 percent of males aged 70-79 years, and in 75 percent or males aged 80 years or older. Some female premutation carriers may have diminished ovarian reserve (DOR), premature ovarian failure and FXTAS.

It is important to bear in mind that women who have approximately 55 to 200 repeats. There is no clear cut-off between the upper limit of normal and the lower limit of the premutation range. Accordingly, cases with 45-55 repeat copies fall into the so called “gray zone.” In some cases, premutations expand from generation to generation such that over time they ultimately express as full Fragile X syndrome. The larger the premutation in cases that fall in the “gray zone”, the greater is the risk of subsequent expansion to a full mutation in the offspring.

Boys with full FMR1 mutation (Fragile X syndrome) will almost routinely have moderately severe mental retardation. They will tend to have a characteristic facial appearance with a long face, enlarged cranium, protruding ears and an elongated face with a protuberant chin and forehead. Affected boys after puberty tend also to experience enlargement of the scrotum and laxicity of joints. There will also usually be characteristic behavioral problems such as lack of impulse control, temper tantrums, delay in speech and language development and perseverative speech. Hand biting, hand flapping and attention deficit /hyperactivity are other common manifestations. Fragile X syndrome is also the most common known cause of autism or “autistic-like” behaviors.

Girls with Fragile X on the other hand, tend to only have mild mental retardation. Women who have fewer repeats of the FMR-1 gene usually do not have mental retardation but often will have prematurely diminishing of ovarian reserve (DOR) with early menopause and infertility. Both men and women may develop FXTAS.

While most males with full blown clinical fragile X syndrome are mentally retarded and exhibit some or all the physical and behavioral characteristics, only about one third of females are mentally retarded. Another one third are partially mentally impaired, and the remaining third are unaffected.

Fragile X syndrome is diagnosed through DNA testing of cells using one of two methods:

1. Polymerase Chain Reaction (PCR) or
2. Southern blot analysis

Both methods exhibit a high degree of interpersonal variability and thus when it comes to interpreting results, there are significant limitations. This is especially the case when diagnosing a “carrier state.” Interpretation is further complicated by the presence of other fragile sites in the same region of the X chromosome.

It is recommended that in the following circumstances, patients undergoing assisted reproduction be tested for Fragile-X:

• All mentally challenged individuals, those who are autistic, and in cases of developmental delay
• Women with unexplained premature reduction in ovarian reserve or premature ovarian failure (menopause)
• Individuals who have physical or behavioral characteristics of fragile X syndrome
• Those with a family history of fragile X syndrome
• Those with a family history of mentally challenged male or female relatives where no definitive cause has been ascertained.
• Offspring of known carrier mothers

Prenatal diagnosis can be made by 2nd trimester amniocentesis, which yields definitive results. In contrast, results obtained from 1st trimester chorionic villus sampling (CVS) should be interpreted with caution, because the status of the FMR1 gene often will not fully manifest in chorionic villi until the second trimester.

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Herewith are  online links to 2  E-books recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1. From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) ; https://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link ;https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

If you are interested in having an online consultation with me, please contact my assistant, Patti Converse at 702-533-2691 or email her at concierge@sherivf.com\

I

Thank you for sharing your IVF treatment details. From what you’ve described, you are 38 years old and have recently undergone your second IVF cycle, during which three cleaved embryos of reasonable quality were transferred, but unfortunately, conception did not occur. In your first cycle, a single good-quality embryo was transferred, but no others were available for freezing. You currently have three frozen embryos, which, based on your description, are cleaved embryos rather than blastocysts. I understand your concern about the potential for unsuccessful implantation with these embryos.

Additionally, you mentioned the presence of an endometrial polyp identified on ultrasound during stimulation, which has not yet been removed. You also noted that the three frozen embryos have not undergone PGT (Preimplantation Genetic Testing).

Based on your situation, I recommend that the frozen cleaved embryos be cultured to the blastocyst stage and thereupon undergo PGT-A testing so only the good are selectively transferred. However, if these embryos are in fact at the blastocyst stage of development, I would advise against performing a biopsy for PGT, as the process of thawing, biopsying, re-freezing  them only to have to thaw them again for the embryo transfer can cause trauma, which may reduce the chances of success. I would suggest transferring them as is and hoping for the best.

Regarding the endometrial polyp, I strongly suggest it be removed hysteroscopically before proceeding with another embryo transfer to ensure the best possible outcome.

If the transfer of these frozen embryos does not result in at least one viable pregnancy, I would recommend scheduling a detailed online consultation with me.  I have successfully assisted many patients in the UK and would be happy to provide further guidance and support as needed.

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Herewith are  online links to 2  E-books recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1. From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) ; https://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link ;https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

If you are interested in having an online consultation with me, please contact my assistant, Patti Converse at 702-533-2691 or email her at concierge@sherivf.com\

Not to my knowledge!

Sorry!

Geoff Sher

I don’ think it is available presently. WE used to use Tetracycline hydrochloride 5%…cant get it any longer.

Sorry!

Geoff Sher

This sounds like cervical incompetence . You likely leaked fluids after the membranes ruptured and the fetus was infected. This is something that can be treated through the insertion of a cervical cerclage. Discuss it with your Obstetrician.

Geoff Sher

I need to have more information. An important consideration is “how long have you been estrogen-depleted”. IOW how long have you been not having periods (amenorrhea). The reason I say this is that women who have been anesgtrogenic for >6moths, often have depletion of endometrial estrogen receptivity and will not develop an adequate estrogen-induced lining until they have had cyclical HRT for at least 3-4 months. This wil reactivate estrogen receptivity and solve the problem. There could be other reasons for a non-receptive endometrium as well…see below).

My preference for hormonal endometrial stimulation is as follows:

• Cycle Start: To begin, t birth control pills (like Marvelon, Desogen ,Lo-Estrin etc.,)for about 10 days. Then patient commence 0.75mg Dexamethasone daily OR 10mg prednisone BID at cycle start. This is continued to the 10^th week of pregnancy (tailed off from the 8^th to 10^th week) or as soon as pregnancy is ruled out
• Hormone Kickstart: After 10 days on BCP , start daily injections of a GnRH antagonisd (e.g., upron/Lucrin/decapeptyl/ Superfact/ Buserelin) .
  
•  Monitoring Progress: Ultrasounds and blood tests done serially.
•  Hormone therapy: Delestrogen (estradiol valerate-E2V) 4mg IM is injected, twice weekly (on Tuesday and Friday), commencing within a few days of Lupron/Lucrin/Superfact, Decapeptyl-induced menstruation. Blood is drawn on Monday and Thursday for measurement of blood [E2].  This allows for planned adjustment of the E2V dosage scheduled for the next day. The objective is to achieve a plasma E2 concentration of 500-1,000pg/ml and an endometrial lining of >8mm, as assessed by ultrasound examination done after 10 days of estrogen exposure i.e., a day after the 3^rd dosage of Delestrogen.  The twice weekly, final (adjusted) dosage of E2V is continued until the 10^th week of pregnancy or until  pregnancy is discounted by blood testing or by an ultrasound examination. Dexamethasone/Prednisone is  0.75 mg is taken orally until the 10th week of pregnancy.and oral folic acid (1 mg) is taken daily commencing with the first E2V injection and is continued throughout gestation.
• Antibiotic prophylaxis:  Ciprofloxin 500mg BID orally starting with the initiation of Progesterone therapy and continuing for 10 days.
• Luteal support: commences on  6 days prior to the FET, with intramuscular progesterone in oil (PIO) at an initial dose of 75-100  mg (-Day 1). Daily administration- is continued until late in  the evening of Day 5 ( I suggest 10.00PM-11.00PM) . Daily PIO (75mg-100mg) is continued until the 10^th week of pregnancy, or until a blood pregnancy test/negative ultrasound (after the 6-7^th gestational week), discounts a viable pregnancy. Also, commencing on the day following the FET, the patient inserts one (1) vaginal progesterone suppository (100 mg) in the morning  + 2mg E2V vaginal suppository (in the evening) and this is continued until the 10^th week of pregnancy or until pregnancy is discounted by blood testing or by an ultrasound examination after the 6-7^th gestational week.
• Blood pregnancy Testing:  Blood pregnancy tests are performed 13 days and 15 days after the first PIO injection was given
• Timing the  FET: This  is performed as early as possible on the morning of Day-6  

Hope this helps. If you wish to talk to me, call my assistant, Patti Converse (702-533-2691) and set up an online consultation to discuss.

Geoff Sher

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• THE IMPACT OF A THIN UTERINE LINING ON EMBRYO IMPLANTATION: THE BENEFITS OF VIAGRA THERAPY

Back in 1989, I conducted a study that examined how the thickness of a woman’s uterine lining, known as the endometrium, affected the successful implantation of embryos in IVF patients. The study revealed that when the uterine lining measured less than 8mm in thickness by the day of the “hCG trigger” in fresh IVF cycles, or at the start of progesterone therapy in embryo recipient cycles (such as frozen embryo transfers or egg donation IVF), the chances of pregnancy and birth were significantly improved. In my opinion, an ideal estrogen-promoted endometrial lining should measure at least 9mm in thickness, while a lining of 8-9mm is considered “intermediate.” In most cases, an estrogenic lining of less than 8mm is unlikely to result in a viable pregnancy.

A “poor” uterine lining typically occurs when the innermost layer of the endometrium, called the basal or germinal endometrium, fails to respond to estrogen and cannot develop a thick enough outer “functional” layer to support optimal embryo implantation and placenta development. The “functional” layer makes up two-thirds of the total endometrial thickness and is the layer that sheds during menstruation if no pregnancy occurs.

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

1. Damage to the basal endometrium due to:

1. • Inflammation of the endometrium (endometritis) often resulting from retained products of conception after abortion, miscarriage, or birth.
   • Surgical trauma caused by aggressive uterine scraping during procedures like D&C.

1. Insensitivity of the basal endometrium to estrogen due to:

1. • Prolonged or excessive use of clomiphene citrate.
   • Prenatal exposure to diethylstilbestrol (DES), a drug given to pregnant women in the 1960s to prevent miscarriage.

1. Overexposure of the uterine lining to ovarian male hormones, mainly testosterone, which can occur in older women, women with diminished ovarian reserve, and women with polycystic ovarian syndrome (PCOS) who have increased LH biological activity. This hormonal imbalance leads to the overproduction of testosterone in the ovary’s connective tissue, further exacerbated by certain ovarian stimulation methods used in IVF.
2. Reduced blood flow to the basal endometrium, often caused by:

1. • Multiple uterine fibroids, especially those located beneath the endometrium (submucosal).
   • Uterine adenomyosis, an abnormal invasion of endometrial glands into the uterine muscle.

“The Viagra Connection”

Eighteen years ago, I reported on the successful use of vaginal Sildenafil (Viagra) in treating women with implantation dysfunction caused by thin endometrial linings. This breakthrough led to the birth of the world’s first “Viagra baby.” Since then, thousands of women with thin uterine linings have been treated with Viagra, and many have gone on to have babies after multiple unsuccessful IVF attempts.

Viagra gained popularity in the 1990s as an oral treatment for erectile dysfunction. Inspired by its mechanism of action, which increases penile blood flow through enhanced nitric oxide activity, I investigated whether vaginal administration of Viagra could improve uterine blood flow, deliver more estrogen to the basal endometrium, and promote endometrial thickening. Our findings confirmed that vaginal Viagra achieved these effects, while oral administration did not provide significant benefits. To facilitate treatment, we collaborated with a compound pharmacy to produce vaginal Viagra suppositories.

In our initial trial, four women with a history of poor endometrial development and failed conception underwent IVF treatment combined with vaginal Viagra therapy. The Viagra suppositories were administered four times daily for 8-11 days and stopped 5-7 days before embryo transfer. This treatment resulted in a rapid and significant improvement in uterine blood flow, leading to enhanced endometrial development in all four cases. Three of these women subsequently conceived. In 2002, I expanded the trial to include 105 women with repeated IVF failure due to persistently thin endometrial linings. About 70% of these women responded positively to Viagra therapy, with a notable increase in endometrial thickness. Forty-five percent achieved live births after a single cycle of IVF with Viagra treatment, and the miscarriage rate was only 9%. Women who did not show improvement in endometrial thickness following Viagra treatment did not achieve viable pregnancies.

When administered vaginally, Viagra is quickly absorbed and reaches the uterine blood system in high concentrations. It then dilutes as it enters the systemic circulation, explaining why treatment is virtually free from systemic side effects.

It is important to note that Viagra may not improve endometrial thickness in all cases. Approximately 30-40% of women treated may not experience any improvement. In severe cases of thin uterine linings where the basal endometrium has been permanently damaged and becomes unresponsive to estrogen, Viagra treatment is unlikely to be effective. This can occur due to conditions such as post-pregnancy endometritis, chronic inflammation resulting from uterine tuberculosis (rare in the United States), or extensive surgical damage to the basal endometrium.

In my practice, I sometimes recommend combining vaginal Viagra administration with oral Terbutaline (5mg). Viagra relaxes the muscle walls of uterine spiral arteries, while terbutaline relaxes the uterine muscle itself. The combination of these medications synergistically enhances blood flow through the uterus, improving estrogen delivery to the endometrial lining. However, it’s important to monitor potential side effects of Terbutaline such as agitation, tremors, and palpitations. Women with cardiac disease or irregular heartbeat should not use Terbutaline.

Approximately 75% of women with thin uterine linings respond positively to treatment within 2-3 days. Those who do not respond well often have severe inner ( (basal) endometrial lining damage, where improved uterine blood flow cannot stimulate a positive response. Such cases are commonly associated with previous pregnancy-related endometrial inflammation, occurring after abortions, infected vaginal deliveries, or cesarean sections.

Viagra therapy has been a game-changer for thousands of women with thin uterine linings, allowing them to successfully overcome infertility and build their families.

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ADDITIONAL INFORMATION:

Herewith are  online links to 2  E-books recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1. From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) ; https://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link ;https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

If you are interested in having an online consultation with me, please contact my assistant, Patti Converse at 702-533-2691 or email her at concierge@sherivf.com\

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