OBJECTIVES:
To evaluate whether three daily doses of GnRH agonist (Inj. Lupride 1 mg SC) administered 6 days after oocyte retrieval increases ongoing pregnancy rates following embryo transfer (ET) in cycles stimulated with the long GnRH agonist protocol.
SETTINGS AND DESIGN:
Prospective randomized controlled study in a tertiary care center. MATERIALS AND METHODS: Four hundred and twenty six women undergoing ET following controlled ovarian stimulation with a long GnRH agonist protocol were included. In addition to routine luteal’ phase support (LPS) with progesterone, women were randomized to receive three 1 mg doses of Lupride 6 days after oocyte retrieval. Computer’ generated randomization was done on the day of ET. Ongoing pregnancy rate beyond 20th week of gestation was the primary outcome measure. The trial was powered to detect a 13% absolute increase from an assumed 27% ongoing pregnancy rate in the control group, with an alpha error level of 0.05 and a beta error level of 0.2.
RESULTS:
There were 59 (27.69%) ongoing pregnancies in the GnRHa group, and 56 (26.29%) in the control group (P = 0.827). Implantation, clinical pregnancy and multiple pregnancy rates were likewise similar in the GnRHa and placebo groups. CONCLUSIONS: Three 1 mg doses of Lupride administration 6 days after oocyte retrieval in the long protocol cycles does not result in an increase in ongoing pregnancy rates.
INTRODUCTION
Luteal “phase deficiency occurs frequently in ovulation induction cycles using pituitary down” regulation with a GnRH agonist as well as in those using GnRH antagonists for ART. To cope with this problem, different regimens of luteal’ phase support have been suggested. Most of these regimens involve use of two therapeutic agents, HCG and progesterone, used separately or together in different doses and routes of administration. Adjuvants have been tried to further better the luteal support with either of these two agents used primarily for luteal support such as estradiol, aspirin, vitamin C etc., Some recent data, however, have suggested a beneficial effect of GnRH agonist administered in the luteal phase on ART outcomes. The mechanism of the presumed beneficial effect of luteal’ phase GnRH agonist administration is not clear.
and may be due to the drug action at multiple levels. It was hypothesized that GnRH agonist may support the corpus luteum by stimulating the secretion of LH by pituitary gonadotroph cells or by acting directly on the endometrium through the locally expressed GnRH receptors or by directly acting on the embryo itself. The administration of a single dose of GnRH agonist in the luteal phase was also shown to increase pregnancy, implantation, delivery and birth rates in recipients of donated oocytes in whom ovulation was suppressed and the corpus luteum was thus absent, suggesting a direct effect of GnRH agonist on the endometrium or the embryo. Despite stressing the importance of this finding, properly conducted trials to evaluate the reproducibility of these results were advised before widespread adoption of this simple yet seemingly effective strategy. In this report, we present a prospective randomized, controlled trial aimed to assess the effect of a three 1 mg doses of Inj. Lupride, administered 6 days after oocyte retrieval, on the probability of ongoing pregnancy rates following embryo transfer (ET) in cycles stimulated with a long GnRH agonist protocol.
Summary:
Reporting two cases of primary amenorrhea with primary infertility and underlying hypogonadotropic hypogonadism (HH). In both cases ovulation induction was initiated with highly purified human menopausal gonadotropin (hMG) in doses starting from 75 IU to the highest of 450 IU per day for 34 and 23 days respectively, with no follicular response and steroidogenesis. In the same cycle the gonadotropin preparation was changed to recombinant follicle stimulating hormone (r-hFSH) and recombinant luteinizing hormone(r-hLH) in doses of 225IU and 75IU respectively in the first case for 9 days and 150IU and 75IU respectively for 6 days in the second case, after which dominant follicles developed with subsequent ovulation. Both treatment cycles resulted in term live births. Hence, it appears that recombinant gonadotropins are more consistent in their activity as compared to the available urinary gonadotropins.
Background:
Hypogonadotropic hypogonadism is a condition of failure of gonadal function, characterized by low or undetectable levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) with subsequent estradiol deficiency and primary amenorrhea. The gonadotropin deficiency is owing to absence of pulsatile secretion of hypothalamic GnRH, or pathology within or around the pituitary which leads to complete arrest of ovarian follicular growth.
Pregnancy can be achieved in this condition through ovulation induction with exogenous gonadotropins. Gonadotropins were developed for clinical use for the first time in 1957, from urine of menopausal women. However, there were multi faceted problems in using gonadotropins recovered from this source. These problems ranged from collection of large quantities of urine to presence of urinary proteins in purified extracts, low specific activity causing inconsistency in the amount of gonadotropin, along with batch to batch variability. Ever since this development, scientists have been on the lookout of a more consistent preparation of gonadotropins which could take care of all these deficiencies. Recombinant gonadotropins were developed by the recombinant DNA technology and launched first time for clinical use in 1995 after approval by the European Medicines Evaluation Agency. These gonadotropins had batch to batch consistency with minimal variability in drug effect and high specific activity.
We are presenting here two cases of HH, who were started for ovulation induction with urinary hMG with almost no follicular response even after 34 and 23 days of administration respectively. Surprisingly, on changing the type of gonadotropin further to recombinant FSH and recombinant LH during the same cycle, follicular response was achieved within 9 and 6 days in both cases respectively, to cause successful ovulation and subsequent live birth.
Case presentation:
Case-1 A 30 years old female with primary amenorrhea came with secondary infertility. She had one miscarriage which she conceived through ovarian stimulation and intrauterine insemination. Hormonal assay diagnosed her as a case of hypogonadotrophic hypogonadism. Injections of hMG were given starting from 75 IU/day in incremental doses, up to 450 IU/day for duration of 34 days with no recruitment of follicles. Subsequently r-hFSH and r-hLH were used in 3:1 ratio (225:75 IU) replacing hMG following which ovulation of two dominant follicles was achieved with 9 days of stimulation.
Case-2 Our second case was a 32 year old hypogonadotrophic hypogonadic woman with primary amenorrhea and primary infertility. Ovulation induction was initiated with 75 IU/day of hMG and the dosage was increased to 450 IU with no recruitment of follicles till 23 days of drug administration. We switched over to r-hFSH and recombinant r-hLH in 2:1 ratio (150:75 IU) and administered these for 6 days on a daily basis after which 2 dominant follicles were obtained, which ovulated following human chorionic gonadotropin (hCG) trigger.
Investigations:
|
|
Case-1 |
Case-2 |
|
AMH(pMol/L) |
10.2 |
9.4 |
|
FSH(mIU/ml) |
0.3 |
0.41 |
|
LH(mIU/ml) |
0.1 |
0.72 |
|
Estradiol(pg/ml) |
10 |
20 |
|
Pre-hCG estradiol(pg/ml) |
329 |
137 |
Differential diagnosis:
Ovarian dysgenesis (OD) is the most common differential diagnosis due to similar clinical presentation of primary amenorrhea, delayed puberty and infertility.
Serum gonadotropin levels are most significant in order to differentiate between the two. OD is characterized by high FSH levels with irregular release, less elevated and more stable LH level, while HH reveals sharply reduced monotonous FSH and LH levels.
Outcome:
In both patients, 2 dominant follicles were formed after change over to r-hFSH and r-hLH. Pre-ovulatory estradiol levels were 329pg/ml and 137pg/ml in case 1 and 2 respectively. Both of them conceived with twin pregnancy and subsequent live births at term gestation.
Discussion:
In normo-gonadotropic females basal FSH and LH is sufficient for ovarian response, hence, stimulation with FSH alone leads to optimal folliculogenesis with adequate steroid production. However, in HH the deficiency of FSH and LH both is profound and as per “two cells two gonadotropin” theory both the gonadotropins are essential for adequate follicular growth and steroidogenesis. Pulsatile GnRH was the first method used for gonadotropin secretion leading to monofollicular ovulation in such patients. Later on pulsatile GnRH agonist was abandoned in favor of hMG due to need for the cumbersome electronic pump, inconvenience of drug administration as well as the side effects and complications of using pulsatile GnRH. Therefore, hMG became the mainstay of treatment as it contained both FSH and LH in 1:1 ratio hence, could provide both the essential gonadotropins in such cases. However, urinary gonadotropins are considered to be inconsistent in their action with variable and low specific activity as compared to recombinant human gonadotropin, which apart from having batch to batch consistency also has very high specific activity. This possibly appears to be the reason of the beneficial effect seen in follicular growth on changing over from hMG to recombinant gonadotropin in both our cases. A recent systematic review and meta-analysis compared the efficacy of urinary gonadotropin to recombinant gonadotropin in intrauterine insemination cycles for women with unexplained infertility and concluded that recombinant preparation was required in half the dose when compared to highly purified urinary preparation to achieve the same pregnancy rate. However, when both gonadotropin where used in the same dose pregnancy rates was significantly lower in the urinary gonadotropin group. Another recent study from Italy compared recombinant gonadotropin to hMG in 70 women with HH and found similar ovulation rates in both groups but significantly higher pregnancy rates in the recombinant gonadotropin group.
Learning points:
Administration of recombinant gonadotropins has shown in most trials to have more consistent action with no batch to batch variability. Addition of r-hLH in minimal doses to r-hFSH appears optimal in terms of folliculogenesis and steroid production to achieve ovulatory response even in cases of extreme gonadotropin deficiency such as in hypogonadotropic hypogonadism.
Introduction
Nearly one-third of the world population is infected with Mycobacterium tuberculosis (MTB) of whom only 10% are known to progress to clinical disease (WHO, 2006). Depending upon the localization of the MTB in an organ, a wide spectrum of tubercular disease is encountered in clinical practice of which female genital TB (GTB) is an important manifestation (Schaefer, 1976; Parikh et al., 1997; Aliyu et al., 2004; Dannenberg and Converse, 2011). Damage to the pelvic organs after clinical GTB is well recognized both in the presence of active disease as well as during the process of healing and fibrosis. The diagnosis can be established in such cases with the help of various microbiologic, radiologic and histopathologic tests along with the clinical presentation. The diagnostic tests have high specificity but a low sensitivity even in the presence of active tuberculosis (TB). A battery of tests may be required to arrive at the diagnosis (Tripathy and Tripathy, 1990; Jindal, 2006; Rozati et al., 2006). The fibrosis and scarring which result as a part of healing lead to the loss of function of the Fallopian tubes, and less commonly of ovaries and endometrium. It is therefore desirable to diagnose and treat GTB as early as possible during the subclinical stage to prevent or at least to minimize the damage to the genital organs. Unfortunately, the conventional tests for the diagnosis of TB during the sub-clinical stages have poor sensitivity and specificity. However, recently the detection of MTB DNA by TB-PCR has shown high sensitivity and specificity for the diagnosis of GTB (Baum et al., 2001; Roy et al., 2003; Bhanu et al., 2005; Rana et al., 2011). We have previously shown that the maximum likelihood estimates of sensitivity and specificity for the diagnosis of GTB with a positive TB-PCR in the endometrial samples were 0.59 and 0.92, respectively (Jindal et al., 2010). In a recent study, the authors have shown that 57% of infertile women in whom the presence of TB was suspected on clinical grounds had a positive endo-TB-PCR test, whereas only 9.5% had a positive test where no clinical ground for suspicion were present (Thangappah et al., 2011). Endometrial TB-PCR (endo-TB-PCR) positivity in the absence of symptoms, and without any demonstrable tubal or endometrial damage, raises the possibility of a false-positive TB-PCR test in the absence of any mycobacterial infection. Empirical treatment, especially in the high-prevalence countries is also fraught with the risks of resistance and other side effects of anti-tubercular chemotherapy. On the other hand, a positive endo-TB-PCR test may also imply the presence of sub-clinical, latent or past disease, which could be managed with anti-tubercular treatment (ATT). This is supported by the limited observations made for both genital and other forms of TB in some recent studies (Cheng et al., 2004; Kulshrestha et al., 2011; Thangappah et al., 2011). Short course chemotherapy is effectively used to treat symptomatic GTB (Jindal et al., 1990). However, for infertile women with GTB, assisted reproduction techniques (ARTs) are also required to achieve pregnancy (Soussis et al., 1998; Jindal, 2006; Singh et al., 2008). The present study was undertaken to examine the fertility of infertile women with positive endo-TB-PCR in the absence of demonstrable damage to the endometrium or the Fallopian tubes after the early institution of ATT.
Materials and Methods
The study was undertaken from the year 2006 to 2010 at an IVF center in northern India. Women from all couples seeking treatment for infertility between 2006 and 2008 were screened for inclusion in the study. All couples were investigated and managed according to the standard protocol followed at the center. Tubal and endometrial evaluation was done either by hysterosalpingography (HSG) or laparoscopy and hysteroscopy. Endometrial samples were obtained by endometrial aspiration or curettage, done as a stand-alone test or along with laparoscopy and/or hysteroscopy. One part of the biopsy of endometrial tissue was subjected to histopathologic examination and the second part was sent to the Laboratory for TB-PCR testing. Endometrial samples were obtained by gentle curettage of the endometrium and kept in sterile containers with normal saline to avoid contamination. Histopathologic examination of endometrial biopsies did not reveal any presence of acid fast bacilli, granuloma formation or other findings suggestive of TB.
PCR testing
Endo-PCR test was arranged with Reliance Life Sciences Pvt. Ltd. Mumbai, a national laboratory providing services all over India, accredited by the American College of Pathologists, with a proficiency test score for TB of 100% in 2007 and 2008. Stringent criteria were used at the laboratory to avoid contamination of results. The test was run in duplicate. Nested PCR against the most conserved region insertion sequence 6110 gene was done employing a Fastprepw sample preparation system (BioMedicals, Cambridge, UK) for mycolic acid cell wall lysis to extract DNA. The PCR assay gave a clear band of 123 base pairs (bp), indicating positivity of a sample. The assay used a cellular gene to rule out false negativity of the samples, with the cellular gene confirming no general DNA degradation in the sample and absence of PCR inhibitors in the sample. One positive and one negative clinical samples were used in every assay to validate the assay and confirm the results. A blank reagent containing no DNA was used to check contamination during PCR by the absence of any PCR fragment in the gel. The assay was also validated by direct sequencing of the PCR product indicating .95% homology with MTB, using NBLAST (www .ncbi.nlm.nih.gov/ blast). The quoted sensitivity of the test is almost 100% and specificity 96 – 99%, with a lower detection limit of 100 TB bacilli/ml (Nolte et al., 1993; Folgueira et al., 1996; Takahashi and Nakayama, 2006)
Patients
Of 3108 infertile couples who reported between 2006 and 2008, the study included 443 (14.2%) women of, 40 years of age who had no symptoms other than infertility, and without any evidence of endometrial or tubal damage on HSG or laparoscopy and hysteroscopy. The reasons for exclusion of the remaining 2665 (85.8%) cases were TB-PCR not done (1244); presence of a tubal factor (552); tubal evaluation not done (248); severe male factor (132); severe and moderate endometriosis (101); endometrial factor (76); previous history of ATT (168); age .40 or previous oophorectomy (91) and those who did not report for followup evaluation (53). Among 443 women who were included, 169 (38.15%) with PCR positive test constituted the study group (Group I) and 274 (61.85%) PCR negative, the control group (Group II). Follow-up assessment was continued for at least 2 years after recruitment in the study up to end of 2010.
Treatment
The study Group I, received standard short course daily ATT consisting of the intensive phase of 2 months of four drugs (isoniazid, H 300 mg; rifampicin, R 450 – 600 mg; ethambutol, E 800 – 1200 mg and pyrazinamide, Z 1200 – 1500 mg) followed by the maintenance phase of 4 months comprising the same doses of isoniazid and rifampicin (2HRZE, 4HR). The first-line treatment for non-tubal infertility consisted of ovulation induction along with IUIin PCR negative Group II and also in PCR positive Group I, after completion of ATT. IVF was undertaken for refractory infertility for 32 of Group I and 45 of Group II women; the remaining 150 women did not opt for IVF and wished to wait longer for various personal reasons. In brief, the IVF procedure consisted of employing stimulation protocols using GnRH analogs and urinary or recombinant gonadotrophins. Final maturation trigger was given when at least three lead follicles were .16 mm. Ovum pick up was done 36 h after hCG. All metaphase-2 oocytes were injected with sperm by intracytoplasmic sperm injection. Embryo transfer was done on second/third day and a maximum of three embryos were transferred. Pregnancy was defined as the presence of viable gestational sac on ultrasound examination at 3 – 4 weeks after embryo transfer.
Statistical methods
Details of all cases were recorded on a structured format and analyzed with the help of registered version of SPSS version 13. Group comparisons were made using x2 test (for categorical variables) or Student t-test (for scalar variables). Statistical significance was assessed at P , 0.05. Probability of spontaneous pregnancy (without any IUI or IVF) during the follow-up period was calculated by Kaplan –Meier method, and formal comparisons between different groups were performed using the log-rank test.
What is an ectopic pregnancy? Can I take any measures to reduce my risk? —MK, 31
An ectopic pregnancy is a complication of pregnancy where a newly-formed baby (embryo) gets implanted outside the uterus. About 1 to 3% of all pregnancies are ectopic in location and of these 98% occur in the fallopian tubes. Apart from the fallopian tube, ectopic pregnancy can also occur in the cervix, ovaries and abdomen. An embryo implanted in places other than the uterus can cause great tissue damage in its effort to get sufficient supply of blood for its growth. It needs to be terminated immediately to prevent serious haemorrhage in the woman.
What leads to an ectopic pregnancy?
Hair-like cilia located on the internal surface of the fallo – pian tubes are responsible for carrying the fertilised egg to the uterus. This in normal circumstances takes four to five days after ovulation (release of the egg). Any factor which stops this transport results in the live embryo being retained in the tube where it may start growing to form an ectopic pregnancy. The risk factors predisposing a woman to an ectopic pregnancy are fallopian tubal damage caused by pelvic inflammatory disease, chronic pelvic infections and following tubal reconstructive surgeries. In certain women fallopian tube cilia are genetically fewer in number, predisposing them to recurrent ectopic pregnancies. However, in as many as one third to one half, no risk factor can be identified. Previous history of ectopic pregnancy increases the risk of future ectopic pregnancy to about 10% due to damage to the inner lining of the tube.
What safety measures can you take?
To ensure a safer pregnancy following an ectopic one (where the tube has been retained), it is better to conceive in the menstrual cycle where a woman ovulates from the ovary situated on the side of the non-affected tube. For this, sometimes an ultrasound can be used to detect which of the ovaries is releasing the egg. One can try for the next pregnancy soon after resumption of normal menstrual cycle. However, once pregnant, do confirm the site of the pregnancy within a week or 10 days of the missed period to ensure that the embryo has implanted in the uterus. If both the tubes are unhealthy, it may be wiser to resort to IVF where the chances of ectopic pregnancy are lowest.
While going through normal delivery, the baby travels through the birth canal (cervix and vagina) to eventually come out into this world through the introitus (entrance of the vagina). During childbirth, all these structures are stretched extensively to allow the baby to pass through. As the birth canal dilates to accommodate the baby, the structures around it—the bladder and rectum, for example—are also stretched by being pushed outwards. The weight of the baby along with strenuous pushing weakens the pelvic-floor muscles, which support the internal organs. When this happens, the bladder, uterus, or bowel or all three can shift from their normal positions. Besides this, the skin between the vagina and anus gets bruised and might tear or be cut (episiotomy) by the doctor to allow the baby out. An episiotomy or vaginal tear might hurt for a few weeks. Extensive tears might take longer to heal.
The most common vaginal symptoms and discomfort a new mum may feel include:
Tackling Incontinence
Pregnancy and birth stretch the connective tissue at the base of the bladder and can cause nerve and muscle damage to the bladder or urethra. This might cause leaking of urine on coughing, straining or laughing (also known as stress incontinence). Fortunately, this problem usually improves within 3 months. In the meantime, do Kegel exercises to strengthen the pelvic floor muscles. Tighten pelvic muscles as if stopping the stream of urine. Initially the muscles don’t appear to move but it is important to go on trying and they will start working. (It’s no differ ent from training your abs or biceps—you want to make your pelvic muscles taut.) Try it for 5 seconds at a time, 4 or 5 times in a row. Work up to keep the muscles contracted for 10 seconds at a time, relaxing for 10 seconds between contractions. Aim for as many sets of 10 repetitions a day at any time during the day, for instance while watching TV or chatting with friends on the phone.
Enjoying Sex Life
Sexual intercourse can be resumed as soon as one desires it and it is comfortable. If delivery causes tearing, or if an episiotomy is done, sexual intercourse should be delayed until the affected area heals to avoid pain. Using Kegel’s exercise while having sex may help make it more enjoyable for both partners especially in the initial phase after child birth, when the vagina is still lax.
In recent years, there has been growing concern regarding the adverse effects of various environmental contaminants and stress on human reproduction. Industrialization, urbanization and rapid economic development have drastically changed the lifestyle and surroundings of humans. Many potentially hazardous chemicals are being released into the environment at an alarming rate, which may negatively influence all aspects of human health including the reproductive system.
MECHANISM OF ACTION
The only way that environmental toxins can cause tissue damage and adversely affect various systems of the body is by direct damage to the cell membrane or its intracellular components. There are compounds which disrupt communication between different cells and if this effect is targeted at the endocrine system, then this may affect fertility and may cause reproductive dysfunction resulting in reproductive anomalies. These are often termed as endocrine disrupting chemicals (EDCs) which cannot be classified by any unique physical or chemical properties but are thought to affect reproduction by their ability to mimic, stimulate, antagonize, alter or displace the effects of endogenous natural hormones.1 Specifically, endocrine disrupters can mimic or antagonize the actions of endogenous hormones either by inducing changes in steroidogenic enzyme expression and/or their activity, or by altering the circulating steroid hormone levels.2-5 Besides the physical, chemical and biological environment which disrupts the hormonal milieu, other factors, such as behavioral and socioeconomic conditions, also have significant impact on human fertility. These possibly act on higher centers and eventually change the paracrine, autocrine and endocrine regulation of hormones affecting fertility.
ENVIRONMENT AND INFERTILITY
Environment represents the totality of physical, chemical, behavioral and socioeconomic factors that constitute the external milieu surrounding the human organism. Environment has both positive and negative influences that can affect every aspect of human health and development. Many reviews over the past few years have focused on environmental factors as possible harmful influences on fertility. The possible mechanisms by which these factors can adversely influence fertility6 can be broadly classified into three main categories:
Physical Environment
Seasonal variation in fertility has been described by several authors. However, the evidence supporting this view is not found to be conclusive enough. Photoresponsiveness though seen in some individuals is not considered to be a universal phenomenon and hence leads to inconsistent results. Some seasonality has been reported in IVF success also. In two European centers with 8,184 cycles, the lowest pregnancy rate of 25.7 percent was seen in July as compared to 35.5 percent in December. However, others observed no significant seasonal variation in IVF success rate in their analysis.
In a Danish study, male exposure to heat and female exposure to noise were associated with poor reproductive outcome. Even frequent changes in time zone as experienced by flight attendants was found to be associated with slightly increased incidence of spontaneous abortions, though the findings were not consistent. Lipscomb et al. reported increased incidence of intrauterine growth retardation (IUGR) in women working in electronics industry. However, all these studies are small and inconclusive and no significant associations can be established.
A positive IgG rubella indicates a past infection or a high titre due to immunisation and will remain positive. A positive IgM indicates a recent infection and is more important with regards to outcome of pregnancy. Your test may be positive from the past or due to recent MMR immunisation. Repeat titres at 4-6 weeks and a rise in titres by 4 fold from previous value are significant. Did you ever have fever with rash and joint pains? Don’t worry or misinterpret your reports. Ask your obstetrician to check the reports for you.
Abha Majumdar, Tejshree Singh
INTRODUCTION
Hysteroscopy is a minimally invasive intervention that can be used to diagnose and treat many intrauterine and endocervical problems. Hysteroscopic polypectomy, myomectomy, and directed endometrial biopsy are just a few of the commonly performed procedures. Given their safety and efficacy, diagnostic and operative hysteroscopy have become standards in gynecologic practice.
SURGICAL ANATOMY
Endometrial Polyps
1. Endometrial polyps are localized overgrowths of the endometrium that project into the uterine cavity. They develop because of excessive multiplication of the endometrial cells, may be hormonally dependent and increase in size depending upon estrogen levels.
2. Polyps may be sessile or pedunculated and rarely include areas of neoplastic growth. Specifically, adenomatous hyperplasia and endometrial adenocarcinomas have been reported in only 0.6% of cases of endometrial polyps.
3. They can usually be detected on an ultrasound scan on second or third post-menstrual day or in mid-cycle, when estrogen levels are maximal, and the endometrium is echogenic.
4. The prevalence of polyps is estimated to be 10 to 24% in hysterectomy samples. Endometrial polyps are rare among women younger than 20 years of age.
5. The incidence of these polyps rises steadily with increasing age, peaks in the fifth decade and then declines after menopause.
Fibroids
1. These are well-circumscribed, non-cancerous tumors arising from the myometrium of the uterus. In addition to smooth muscle, leiomyomas are also composed of extra-cellular matrix, i.e. collagen, proteoglycan, fibronectin.
2. Fibroids are the most common solid pelvic tumors in women, causing symptoms in approximately 25% of reproductive age women. The overall prevalence increases to over 70%, inclusive of asymptomatic fibroids. These are usually detected in women in their 30s and 40s and may shrink after menopause in the absence of post-menopausal estrogen replacement therapy.
3. These are classified by their location in the uterus.
A. Subserosal ones are located just under the uterine serosa and may be pedunculated or sessile.
B. Intramural fibroids are found predominantly within the myometrium but may distort the uterine cavity or cause an irregular external uterine contour.
C. Submucous fibroids are located just under the uterine mucosa and, may be either pedunculated or sessile.
4. Tumors in subserosal and intramural locations comprise the majority (95%) of all leiomyomas; submucous leiomyomas make up the remaining 5%.
5. Although this classification scheme is widely used by clinicians, it suffers from the limitation that few leiomyomas are actually a single “pure” type. Most leiomyomas span more than one anatomic location and, therefore, are hybrids, e.g. a predominantly intramural leiomyomas with a submucous component.
6. Transformation of uterine leiomyomas to uterine leiomyosarcomas is extremely rare, and, in fact, many researchers and clinicians believe this type of transformation never occurs. Uterine leiomyosarcomas are found in approximately 0.1% of women with leiomyomas and are reported to be more frequently associated with large or rapidly growing fibroids.
Thickness of the Uterine Wall
Thickness of the Uterine Wall1 This knowledge allows the surgeon to manipulate the surgery on the basis of the area of the uterus where surgeon is operating. The uterus is longer and thicker in reproductive-aged women than in postmenopausal women.
PREOPERATIVE PREPARATION
Appropriate surgical management always begins with accurate history taking, physical examination, and careful workup of the suspected problem. In preparation for hysteroscopic procedures, the following considerations may be useful.
LAB STUDIES: Apart from general health tests, the following tests are required
• Blood typing and screening: With the risk of hemorrhage approaching 7-8% in some surgical hysteroscopic procedures, a sample in the blood bank increases the efficiency of access to replacement of blood products, if needed.
• Electrolyte determinations: In patients with medical disorders that predispose them to metabolic abnormalities, e.g. diuretic use, electrolytes should be tested preoperatively. Some surgeons routinely obtain baseline levels in case a significant deficit of distention medium occurs especially with a hyposmolar solution, whereas most obtain electrolyte levels intraoperatively or postoperatively only if a clinically significant fluid deficit occurs. The ultimate decision should be based on the type of case, the surgeon’s skill, the suspected fluid absorption, and the ability to accurately ascertain fluid deficits in the operating room.
• Determination of human chorionic gonadotropin (hCG) levels is mandatory in any woman of reproductive age to exclude pregnancy.
• Cervical cultures: May be taken depending on prevalence of Chlamydia and gonorrhea in the population and a wet smear for bacterial vaginosis and trichomoniasis are recommended.
• Papanicolaou test: A normal or abnormal Pap smear that has been appropriately evaluated is required because trauma to the cervix may alter the appearance of any existing abnormalities.
IMAGING STUDIES
• Ultrasound of the lower abdomen is done postmenstrually to evaluate the size and shape of the uterus, endometrial thickness, fibroids (location (Figs 1 and 2), whether distorting the uterine cavity Fig. 3) as well as endometrial polyps (Fig. 4).
• Hysterosalpingogram or sonohysterosalpingogram is used for evaluating the uterine cavity and patency of fallopian tubes. However, to selectively look at the uterine cavity, sonohysterography or saline-infused sonography and 3-D ultrasound appear to have a better predictive value than that of hysterography for determining the location and size of fibroids and endometrial polyps (Fig. 5).
• CT scan or MRI: These are not usually needed unless the findings on ultrasound are inconclusive.
ANTIBIOTIC PROPHYLAXIS
Prophylactic antibiotics are not indicated unless the patient has clinically significant cardiac disease or a history of tubal occlusion due to pelvic inflammatory disease.
DIFFICULTIES
Cervical Stenosis
In patients with known cervical stenosis or tortuous cervical canals, preoperative vaginal or oral misoprostol, or intraoperative vasopressin 1% administered paracervically may be used to assist in cervical dilation.
Large Uterus
A uterus longer than 10 cm makes the case difficult, because the length of the hysteroscope is typically 35 cm and it must traverse the length of the uterus, cervix, and vagina while maintaining a position outside the introitus with enough distance to attach the camera and manipulate the fluid inflow-outflow valves and the surgical instruments. Also, maintaining intrauterine pressures in large cavities is more difficult than with small cavities.
ABSTRACT
OBJECTIVES: The objective of the study is to evaluate the efficacy of gonadotropin releasing hormone (GnRH) antagonist in improving clinical pregnancy rate in gonadotropin stimulated intrauterine insemination (IUI) cycles in patients of unexplained infertility. STUDY DESIGN: This was a prospective, randomized case–controlled study. SETTINGS: The study was conducted in the infertility clinic of a tertiary care center. MATERIALS AND METHODS: Four hundred twenty seven women undergoing IUI following controlled ovarian stimulation with gonadotropins (recombinant follicle stimulating hormone [r FSH] 75 IU/day) were randomly divided into two groups. Women in Group I received GnRH antagonist (Cetrorelix 0.25 mg/day) in a multiple dose flexible protocol. Women in Group II received r FSH alone. Ovulatory trigger was given with human chorionic gonadotropin 5000 IU when dominant follicle was ≥18 mm. IUI was performed within 44–48 h. Both groups received similar luteal phase support. Primary outcome measure was clinical pregnancy rate. The trial was powered to detect an absolute increase in clinical pregnancy rate by 13% from an assumed 20% clinical pregnancy rate in the control group, with an alpha error level of 0.05 and a beta error level of 0.20. RESULTS: Clinical pregnancy rate in Groups I and II was 27.6% (n = 56) and 26.5% (n = 54), respectively (P=0.800). Ongoing pregnancy and multiple pregnancy rates were likewise similar between the groups. CONCLUSIONS: Addition of GnRH antagonist to gonadotropin stimulated IUI cycles results in no significant difference in clinical pregnancy rate.
INTRODUCTION
Unexplained infertility contributes to about 10–30% of subfertility, depending on diagnostic criteria. Intrauterine insemination (IUI) combined with controlled ovarian stimulation (COS) has been established as a first-line treatment for couples with unexplained infertility. The rationale of COS and IUI is to increase the number of available female and male gametes at the site of fertilization by achieving two to three dominant follicles, followed by a perfectly timed insemination. The use of IUI with COS in a well selected group of patients with unexplained infertility results in comparable cumulative pregnancy rate when compared to in vitro fertilization (IVF) and hence appears more cost effective.
To increase the chances of success in terms of pregnancy rate in COS IUI cycles, various therapeutic approaches have been tried by various researchers, such as different ovarian stimulation protocols, double insemination, and prevention of premature luteinizing hormone (LH) surge. According to the Cochrane review on ovarian stimulation protocols for IUI in the women with subfertility, use of gonadotropins for COS in IUI results in higher pregnancy rate than clomiphene citrate-stimulated cycles (odds ratio [OR] 1.8, 95% confidence interval [CI] 1.2–2.7). A recent meta-analysis clearly indicated that double insemination does not result in higher clinical pregnancy rate compared with single IUI in couples with unexplained infertility. Double insemination has been suggested by researchers because of the hypothesis that capacitated sperms in the inseminate are active for only 2–3 h, so they may not be able to back up ovulation which takes place in between the next 20 and 24 h. However, it appears that precise timing of insemination in relation to ovulation so as to enable active sperms to reach and fertilize the oocyte should obviate the need for double insemination.
Premature LH surge is defined as the surge that precedes the triggering of ovulation iatrogenically. Prospective data have shown that premature LH surge occurs in almost 23% of COS cycles (95% CI 22–43%), which appears quite significant and can interfere with the optimal timing of the insemination. LH surge can be effectively prevented by administering a gonadotropin releasing hormone (GnRH) agonist or GnRH antagonist. Use of GnRH agonist is not recommended in IUI cycles because of prolonged administration of injections prior to and during stimulation to achieve complete downregulation of GnRH receptors, risk of excessive follicular stimulation, and higher cost and inconvenience to the patient.
On the other hand, GnRH antagonist competitively blocks the GnRH receptors and immediately causes pituitary suppression, thereby reduces LH and follicle-stimulating hormone (FSH) secretion within 2–4 h. The efficacy of GnRH antagonist in prevention of premature LH surge is well-established.[17,18] The inhibitory effect of GnRH antagonist is reversible, dose-dependent and is associated with the equilibrium between endogenous GnRH and GnRH antagonist concentration. Cetrorelix (Cetrotide, EMD Serono) and Ganirelix (Antagon, Organon) are the two GnRH antagonists available for clinical use.
The protocols of GnRH antagonist administration in COS IUI cycles are well defined; however; the flexible regimen is the one which is used commonly in mild stimulation cycles.
