The Female Evaluation

The infertility workup of the female partner has undergone several changes over the years but the basics have remained the same. The well-orchestrated female workup can be completed in a single menstrual cycle. At the end of this workup, along with the male data, the clinician should be able to plot a definitive course of treatment. The workup will be divided between female patients who are ovulatory by history and those that are not. Ovulation is presumed if the female has had regular menses every 26-32 days for the last six months. It is important to organize the workup to prevent unnecessary testing. The female workup should start with an initial intake that includes a thorough history, physical examination and a transvaginal pelvic ultrasound. Important historical details include those that might indicate previous exposure to STDs (such as a history of abnormal pap smears), recurrent pregnancy loss and the duration of infertility. Physical examination and pelvic ultrasound will identify patients that have gross pathology requiring surgical treatment prior to further fertility evaluation. For example, a dermoid cyst requiring surgery would allow the surgeon to evaluate tubal patency at the time of surgery rather than ordering an HSG.

Ovarian Reserve Testing
After the initial intake, the next step in the evaluation of the ovulatory female is the evaluation of ovarian reserve. The level of ovarian reserve and the age of the female partner are the most important prognostic factors in the fertility workup. Ovarian reserve is evaluated with a cycle day three FSH and estradiol level. On the third day of bleeding, a simple blood test yields a lot. Normal ovarian function is indicated when the FSH is <10 mIU/mL and the estradiol is <65 pg/mL. If the FSH is >15 mIU/mL, the patient will require egg donation. If the FSH is 10-15 mIU/mL or the E2 is >65 pg/mL, the more sensitive clomiphene citrate challenge test (CCCT) should be performed to further define ovarian reserve.

Tubal Patency
The next step in the ovulatory patient is to confirm tubal patency. This has been done traditionally with the hysterosalpingogram (HSG) and nothing has really improved on this. The HSG is performed at the outpatient radiology department. It involves injecting dye into the uterus and monitoring its "flow back" through the fallopian tubes. Blockages appear as concentrations of dye at the point of the obstruction. This test should be done in the follicular phase of the cycle after bleeding has stopped and before possible ovulation. The ordering physician should personally review the films to confirm findings of the study. Loculation of spill and tubal phimosis indicate that laparoscopy may be helpful. If large hydrosalpinges are identified, they should be clipped or removed laparoscopically prior to in vitro fertilization. Several large studies as well as a recent metanalysis, have confirmed the pregnancy rates with IVF are reduced by half in the presence of hydrosalpinges and that the rates are normalized with salpingectomy. The exact etiology of the phenomenon is not known.

Confirmation of Ovulation
Confirmation of ovulation is unlikely to be helpful in women when a careful history is consistent with ovulation. If there is doubt, a cycle day 21 progesterone with a level greater than 4 ng/mL is indicative of ovulation with most conceptions cycles having levels greater than 10 ng/mL. Alternately, sonographic confirmation of follicle rupture with serial ultrasound can be performed. Some programs use the basal body thermometer (BBT) to predict ovulation. The BBT measures the slight rise in temperature that occurs immediately prior to ovulation. Most physicians prefer to use the urinary ovulation predictor kits as they are more accurate and easy to administer.

Anovulatory Patients
The apparently oligomenorrheic patient should have the cause of their anovulation evaluated thoroughly prior to the initiation of treatment. The initial physical examination should note the presence or absence of goiter, acanthosis nigricans, striae, normal secondary sexual characteristics, Turner’s stigmata, galactorrhea, hirsuitism and abnormalities of the reproductive tract. Ultrasound should note the thickness of the endometrial lining as well as whether the ovaries are polycystic in nature. An endometrial biopsy should be considered if the uterine lining measures greater than 15mm.

Endocrine Evaluation
In anovulatory patients, the initial laboratory evaluation should include random levels of FSH, LH, prolactin, TSH, DHEAS and testosterone. Insulin resistance should be considered in patients that have any of the following: obesity, hirsuitism or acanthosis nigricans on physical exam; polycystic ovaries on ultrasound; inverted FSH/LH ratio or androgen excess on laboratory examination. Evaluation for insulin resistance can be accomplished simply with a 12 hour fasting serum insulin level. A 12 hour fasting serum insulin level of more than 10 mIU/ml signifies hyperinsulinemia in that PCOS subject.

Oocyte Retrieval (Follicle Puncture)

The first IVF baby was born as a result of collecting an egg by laparoscopy. Patrick Steptoe had pioneered the use of the laparoscope in gynaecology - a procedure which is now used extensively but was considered in the late 1970's to be 'a dangerous procedure'. Patrick Steptoe and Robert Edwards achieved the first IVF birth on July 25th 1978, although they had achieved an ectopic pregnancy some time before that. That pregancy was the result of a single egg being collected. The photographs on the right (taken by Patrick Steptoe down the laparoscope) shows a single follicle as a shiny structure towards the bottom left of the ovary. We ocassionally have to yet resort to laparoscopic oocyte retrievals when the ovaries are not accessible with transvaginal ultrasound eg. Meyer-Rokitansky-Kustner-Hauser Syndrome.
Oocyte retrieval is performed approximately 34-36 hours after the hCG injection, immediately before each follicle releases its oocyte. Oocyte retrieval involves a short procedure (lasting 20 to 45 minutes depending on the number of follicles having reached maturity) which is performed transvaginally under ultrasound control (the same way as during the ultrasound monitoring during the stimulation phase). There is therefore no incision or scar involved since the needle is inserted in each follicle by puncturing the ovary directly through the lateral wall at the top of the vagina. Each follicle is punctured and emptied of its fluid by aspiration. The eggs are collected through the vagina under ultrasound control, using a fine needle that is passed through the vagina into the ovary. Fluid from the follicles is sucked through the needle into a test tube and is passed immediately to the adjacent laboratory where the scientist checks for eggs under the microscope. After each aspiration, the sterile test tube containing the aspirated fluid is forwarded to the IVF laboratory, which will do a microscopic search of the fuid for the presence of oocytes. Most eggs are reasonably easy to find as a jelly like mass of cells known as the cumulus surrounds them(see picture). The eggs are then placed in culture fluid (a water based salt solution with added nutrients) in special dishes and put into the incubator at body temperature. If no oocyte is identified, repeated rinsing of the follicle with some millilitres of culture medium generally permits recovery of the oocyte. Oocyte retrieval can be done under a light general anesthesia (usually Propofol) at Rotunda.
The procedure takes 15-30 minutes and most women will have one or several eggs recovered. It is rare for no eggs to be found. After OPU the woman usually remains in the recovery area for about two hours before discharge. Due to the drugs used during the procedure, driving for the next 24 hours is not advisable. Your co-ordination and perception may be impaired and insurance companies may decide not to cover claims that occur during this time. It is not unusual to have some vaginal bleeding, from where the needle passes through the vaginal wall, for the next 24 hours. Mild lower abdominal cramping for the next day or two, due to swelling of the ovaries, is also common and paracetamol can safely be used.

Fertility Tests

Laparoscopy
The laparoscopy is a common outpatient surgical procedure that allows the physician to view reproductive organs such as the tubes, ovary, and uterus, and diagnose conditions causing infertility including endometriosis and tubal blockage(see picture). The laparoscope is a small "telescope like" instrument that is placed through a small incision in the abdomen, usually at the belly button(see picture). Small operative tools are inserted through another small incision at the pubic hairline. The laparoscope usually does not produce noticeable scarring. The abdomen is filled with gas causing it to expand making the internal organs more accessible. Reproductive surgeons undergo extensive advanced microsurgical training with the laparoscope. They are able to perform many, if not most, fertility operations using the laparoscope, which dramatically reduces recovery time, pain cost, and adhesions/scarring. Fertility specialists will usually treat conditions such as endometriosis during the diagnostic laparoscopy. This is one reason that a specialist should perform the laparoscopy when infertility is suspected.

Hysteroscopy
The hysteroscopy is an important tool in the study of infertility, recurrent miscarriage, or abnormal uterine bleeding. Diagnostic hysteroscopy is used to examine the inside of the uterus, also known as the uterine cavity, and is helpful in diagnosing abnormal uterine conditions such as internal fibroids, scarring, polyps, and congenital malformations(see picture). A hysterosalpingogram (an x-ray of the uterus and fallopian tubes) or an endometrial biopsy may be performed before or after a diagnostic hysteroscopy. The first step of diagnostic hysteroscopy involves slightly stretching the canal of the cervix with a series of dilators. Once the cervix is dilated, the hysteroscope, a narrow lighted viewing instrument, similar to but smaller than the laparoscope, is inserted through the cervix and into the lower end of the uterus(see picture). Carbon dioxide gas or special clear solutions like normal saline or glycine are then injected into the uterus through the hysteroscope. This gas or solution expands the uterine cavity, clears blood and mucus away, and enables the physician to directly view the internal structure of the uterus. Diagnostic hysteroscopy is usually conducted at Rotunda under propofol anesthesia. Diagnostic hysteroscopy is usually performed soon after menstruation because the uterine cavity is more easily evaluated and there is no risk of interrupting a pregnancy. A mock transfer or trial transfer may also be done at this time.

Ultrasound
Ultrasound measurements have many applications in the infertility evaluation and are also used for monitoring during in vitro fertilization stimulation cycles. The transvaginal ultrasound (through the vagina) is used frequently because it allows the physician to view the ovaries, uterus, and many other internal organs. The ultrasound produces images similar to an x-ray; however, sound waves are used instead of radiation. Many times dense structures, such as uterine fibroids, are clearly visible on transvaginal ultrasound. The ultrasound is also able to show the follicles on the ovaries as they develop and are ovulated(see picture). The fertility specialist must know the number and size of the follicles during drug-stimulated IVF cycles as this information helps in adjusting medication dosages. Ultrasound is used to measure the width of the endometrium, which must thicken and become more vascular to accept a developing embryo(see picture). It is also used as a means to document pregnancy by visualizing the fetal heartbeat.

CV of the Year

I really loved this Fwd. Please click on the image to magnify it. Enjoy a good laugh & have a happy weekend friends:)

Eggs From Heaven

After a night of drinking, Brian crept into bed beside his wife who was already asleep. He gave her a peck on the cheek and fell asleep. When he awoke he found a strange man standing at the end of his bed wearing a long flowing white robe.

"Who the hell are you?" demanded Brian, "and what are you doing in my bedroom?"

The mysterious Man answered, "This isn't your bedroom and I'm St. Peter".

Brian was stunned, "You mean I'm dead!!! That can't be, I have so much to live for, I haven't said goodbye to my family.... you've got to send me back right away".

St Peter replied, "Yes, you can be reincarnated but there is a catch. We can only send you back as a dog or a hen."

Brian was devastated, but knowing there was a farm not far from his house, he asked to be sent back as a hen. A flash of light later, he was covered in feathers and clucking around pecking the ground.

"This ain't so bad" he thought until he felt this strange feeling welling up inside him.

The farmyard rooster strolled over and said, "So you're the new hen, how are you enjoying your first day here?"

"It's not so bad," replies Brian, "but I have this strange feeling inside like I'm about to explode".

"You're ovulating," explained the rooster, "don't tell me you've never laid an egg before."

"Never," replies Brian. "Well just relax and let it happen."

And so he did, and after a few uncomfortable seconds later, an egg pops out from under his tail. An immense feeling of relief swept over him and his emotions got the better of him as he experienced motherhood for the first time. When he laid his second egg, the feeling of happiness was overwhelming and he knew that being reincarnated as a hen was the best thing that had happened to him..ever!!!

The joy kept coming and as he was just about to lay his third egg he felt an enormous smack on the back of his head and heard his wife shouting, "Brian, wake up you drunken bastard, you're shittin' in the bed."

Clomiphene Challenge Test

Women are born with their lifetime supply of eggs within the ovaries. Each month follicles, each of which contains one egg, are recruited under the influence of follicle stimulating hormone. One follicle will become dominant, develop to maturity, and be ovulated. Ovarian reserve is a measure of the “quality” of the eggs remaining within the ovaries. Ovarian
reserve naturally declines as a woman ages and approaches the menopause. However, diminished reserve can occur in younger women due to perimenopause, genetics, or for unknown reasons.
In the standard infertility evaluation, levels of the hormones FSH, LH, and estradiol are measured on day 3. An elevated FSH level on day 3 is one indication of poor ovarian reserve or that the menopause is approaching. The clomiphene citrate challenge test (CCCT) provides an additional assessment of ovarian reserve. The clomiphene citrate challenge test (CCCT) is a sensitive means to measure ovarian reserve and is often conducted if the FSH level is 10-15 mIU/mL or the E2 is >65 pg/mL. It is performed by measuring the day 3 FSH and estradiol levels, the patient takes 100 mg tablets of Clomiphene Citrate on cycle days 5-9, and her FSH is measured again on day 10. A poor CCCT test, regardless of patient age, indicates that there will be a decreased response to injectable medications in assisted reproductive technology cycles. Pregnancy success rates are lower in these women and there is an increased chance of miscarriage. The clomiphene citrate Challenge Test is routinely performed at our clinic in women aged 38 years or older regardless of how the cycle day 3 levels look. This will identify patients with incipient ovarian dysfunction. The clomiphene citrate challenge test should also be considered in women of any age with otherwise unexplained infertility as approximately 30% will show abnormalities that adversely impact their prognosis with fertility treatment.
A level from 10-12.5 mIU/mL predicts resistance to fertility medications and a diminished prognosis. At 12.5-15 mIU/mL, the prognosis is poor but pregnancies do occur with aggressive treatment. Levels greater than 15 mIU/mL indicate that infertility treatment with the patient’s own eggs is not likely to succeed and that egg donation should be offered. Patients with any FSH level greater than 10 mIU/mL should be referred to a fertility specialist for further evaluation. A poor clomiphene citrate challenge test indicates that it is unlikely that the couple will be successful using in vitro fertilization, IVF. Some clinics do not offer IVF to couples failing the CCCT test and others offer it but clearly explain the poor chance of success. Donor egg IVF is the best option for these couples.

A Cheaper Alternative To IVF

A landmark in the development of fertility treatment was announced by doctors yesterday with the birth of the first babies to be conceived using a revolutionary technique that offers a safer, cheaper alternative to IVF. The twin boy and girl, who were born on 18 October at the Radcliffe Infirmary in Oxford, were conceived using In Vitro Maturation (IVM), a method that dispenses with the use of costly fertility drugs, saving up to £1,500 (INR 120,000) on the normal price of treatment. The technique is also safer for the one in three women among those seeking fertility treatment who have polycystic ovaries, a condition that puts them at high risk of dangerous side effects from fertility drugs. Specialists said the development could make in vitro techniques available to more infertile couples by cutting the cost of treatment. Infertility is estimated to affect one in six couples in the UK but IVF costs around £5,000 (INR 400,000) a cycle and treatment is restricted on the NHS!

Tim Child, a consultant gynaecologist at the Oxford Fertility Clinic and senior fellow in reproductive medicine at Oxford University, who led the work, said: "I think it is a safer, cheaper alternative to IVF for all women. However, for many women the success rates are currently much lower. Research in the future will address this." The Oxford Fertility Clinic is the only one in the UK licensed to use the technique: 20 cycles of treatment have been carried out and four other women are currently pregnant, giving a pregnancy rate of 25 per cent. This is expected to improve with further experience. In addition, without the need for drugs, repeating the procedure would be less taxing on the woman. For standard IVF, the Oxford clinic's pregnancy rate is 45 per cent.

The parents of the babies, who have asked to remain anonymous, were delighted, Mr Child said. At birth the boy, born first, weighed 6lb 11oz and the girl weighed 5lb 14oz. "The parents are ecstatic. They have got absolutely stunning twins. They went home on Tuesday to start their new life together. It is wonderful."

In standard IVF, the woman takes fertility drugs for five weeks to stimulate production of her eggs, which are then collected direct from her ovaries under the guidance of ultrasound, before being fertilised in the laboratory. The drugs cost between £600 and £1,500, with charges often higher in London. The procedure is time consuming and uncomfortable and for the third of women with polycystic ovaries there is a one in 10 risk of severe ovarian hyperstimulation syndrome, a dangerous side-effect that in rare cases can prove fatal.

IVM avoids the use of drugs and instead involves collecting eggs from the ovaries while they are still immature. The eggs are then grown in the laboratory for 24 to 48 hours before being fertilised and replaced in the womb. The technique was pioneered by the University of McGill in Montreal, Canada, where Mr Child spent two years researching and developing it before joining the University of Oxford in 2004. It has also been used in Seoul, South Korea, and Scandinavia. To date about 400 babies have been born worldwide using IVM compared with around two million by IVF. At present the Oxford Fertility Clinic is only offering the treatment to women with polycystic ovaries, but in the long term Mr Child said he hoped to offer the procedure to all women. "When we see patients we say these are the options and it is up to them to decide. We are not offering it to women with normal ovaries at present because we don't get enough eggs from them. It depends on the number of resting follicles and with normal ovaries you don't get so many.

"On average we get four eggs from a woman with normal ovaries compared with 16 from one with polycystic ovaries. The procedure involves a process of attrition – two-thirds mature and two-thirds of those fertilise – so you need a decent number to start with." Research on developing the culture medium in which the eggs are matured in the laboratory could reduce the attrition rate so that fewer eggs are needed. The technique could then become suitable for women with normal ovaries, Mr Child said.

A second drawback of the procedure was that eggs grown in culture had a harder outer shell than those matured in the ovary and were more difficult for sperm to penetrate. The eggs had to be fertilised by ICSI – injecting a single sperm directly into the egg. "We hope to develop the culture medium so the egg doesn't mind being grown in the laboratory and we can use ordinary insemination [mixing eggs and sperm so fertilisation occurs naturally]. But in most IVF clinics, 50 per cent of patients are treated with ICSI anyway," he said. "Anything that reduces the cost of IVF, provided it is safe, means treatment could be available to more people. But this is an emerging technology – it is very early days. The most important thing is that patients get proper information so that they can make a decision on what is best for themselves."