INFERTILITY and ENVIRONMENT

Online Publication in JKIMSU 2012 (Volume-1-No-1-P-24-29)

Abstract:

Environment is coming up as one of the causative factors for many physical and mental diseases. Infertility is not only a medical problem; it is a social and psychological problem as well. Air and soil pollutions are disturbing the male and female reproductive processes in various ways. Endocrine disruptors otherwise called Estrogen Mimics not only induce endometriosis, but can influence the reproductive process by competing with estrogen receptors. Insecticides and environmental toxicants also disrupt the reproductive process. Psychological stress is an important factor for infertility. This is also a stimulating factor for many gynecological conditions like Polycystic Ovary Syndrome (PCOS). In treating the infertile couples, psychological treatment & support are of equal importance as that of medical treatment.

Key Words: Infertility, Environment, Endocrine Disruptors, Psychological Support

Introduction:

Many diseases develop due to parental exposure to offending agents during periconceptional or pre-natal period. The affected individual may be exposed to agents during post-natal or childhood period, too. The former may be called foetal origin of adult disease or Baker’s hypothesis, which states that the process in which stimulus or insults at a critical or sensitive period of development of peri-natal life has permanent effect on the structure, physiology and metabolism of the individual. This can be called the Critical Window of Susceptibility.

Environmental influences may be on the behaviour or on health. The former may be the lifestyle, motivation or interest. Health may be affected by environmental toxicants, environmental hazards, or by endocrine disruptors. Environment may be external or internal (psychological). External environmental effects may be due to nature, people and happenings around. Influence in the workplace is also important. Internal environment comprises of mood, stress, understanding, tranquility and tolerance. Amongst nature, geographic & temporal trends affect fertility, e.g. high temperature affects the testicular function, thereby affecting fertility. Good association is supportive. Criticism, faulty advice is common among women, as it happens in women’s college in girl’s schools or in ladies clubs, which increases stress. Stress in the corporate world & information technology (IT) industry disrupts personal life due to hectic schedule and target fulfilling.

Environmental toxicants are of endless lists, new being added daily. They are found in water, air, soil and food. So, their exposure is almost unavoidable. The pesticides used in crops and the additives used in processed foods are some of these. The ingredients in personal care products like perfumes, soaps and shampoos contain Pthalates, which are detrimental. Exposure to x-rays imposes health hazards, so also some specific medicines and those used for chemotherapies. Some environmental contaminants are also related to infertility. Heavy metal solubles like lead, mercury, cadmium, arsenic and pesticides like DDT, methoxychlorlindane (HPTE), diamethoate, chlordecon; Polychlorinated biphenyls (PCB) in electronic transformers and their metabolites are some such contaminants. Polybrominated Diphenyl Ethers (PBDEs) used in flame-retardants, computer, furniture, clothes and carpets, and Polyvinyl Chlorides (PVCs) and plastics used as containers for food storage are other environmental contaminants. Pthalates used to soften plastics, make-up lotions, shampoos, nail polishes, IV bags, gelatin pill capsules and building materials also act as such contaminants. Bisphenol A, a plastic monomer used in hard polycarbonates, in sports and baby bottles, dental sealants, food and milk carton lining and lenses are important environmental toxicants. Perfluorinated Compounds (PFCs) in Teflon are also very important.

Air pollution is another way of affecting the fertility in both males and females. The car and factory exhausts contain carbon mono-oxide, disulphide and other pollutants, which cause constant air pollutions. Passive smoking, when staying in smoking zones is another way of environmental pollution. Occupational hazards or diseases due to workplace exposure to lead and other heavy metals, as it happens in the paint factories or in farmers using pesticides are also of importance.

Environmental toxicants certainly affect fertility in many ways. In males, they lead to diminished sperm counts and motility, DNA damage and diminished fertilisability. In females, disturbed folliculogenesis, Pre-mature Ovarian Failure (POF), diminished ovarian volume, disturbed oocyte pick-up, unexplained reproductive failure and impaired early embryo developments are some of them. Increased foetal loss, stillbirths, and birth defect syndrome happen more in areas close to agricultures, where pesticide spray is random [1, 2]. Early breast development is also linked to endocrine disrupting chemicals or endocrine disrupting compounds (EDCs) [3]. In-utero exposures to Dichloro Diphenyl Trichloroethane (DDT) have raised the risk of breast cancer in adult life [4]. Thrombotic Thrombocytopenic Purpura (TTP) ) is a rare disorder of the blood-coagulation system, causing extensive microscopic thromboses to form in small blood vessels throughout the body (thrombotic microangiopathy) [4]. Diethylstilbestrol (DES) has a higher incidence of vaginal cancers, infertility, ectopic pregnancy, pre-term delivery, endometriosis and uterine fibroids. Pthalates in women are now linked to pre-term births and pre-cocious puberty [3]. Polychlorinated biphenyls (PCBs), other organochlorines and fine particulate matters are linked to low birth weight and pre-maturity [5].

In recent days, infertility is developing with endocrine disruptors otherwise called endocrine disrupting chemicals, or compounds (EDCs). They are also called Estrogen Mimics. These agents compete with the body’s estrogen receptors and cause mutation of genes in lower animals. They are found in personal care products, toiletries, spermicides and pesticides. Butylated Hydroxyanisole (BHA), the ab andoned form of PVC plastic is one such example. Endocrine disrupting chemicals cause defects as an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action or elimination of hormones that are present in the body, and are responsible for metabolic homeostasis, reproduction and developmental process. Endocrine Disrupting Chemicals, or Compounds (EDCs) are largely related to precocious puberty, abnormal menstruation, endometriosis, pregnancy loss as well as male infertility. Endocrine disruptors can re-programme genes of developing foetus permanently, and the effect can be passed to at least 3 more generations. This is proved in lower animals. In the females endometriosis, ectopic pregnancy, recurrent abortions and lactational failure are considered to be the ill-effects of EDCs. In males, undescended testis, testicular agenesis, hypospadius, micro-penis and poor sperm quality are related to EDCs. With recent decades, the adverse trends in male reproductive health has become evident. In this connection, the a syndrome has been hypothezed as Testicular Dysgenesis Syndrome (TDS) which results from a disturbance in the development of testes during feotal life. This results in declining sperm quality, certain congenital malformations etc. which appears to be probably because of lifestyle and environmental factors than genetic factors. A similar form in female called Ovarian Dysgenesis Syndrome has also been suggested, though the evidence is limited [6]. Diethylstilbestrol (DES) exposure demands special mention. Between 1938-1971, the American gynecologists prescribed DES to pregnant women to prevent recurrent abortion and premature labor, but in 1971, Food & Drug Administration (FDA) banned the use of DES for the above-mentioned indications, because it was found that DES exposure in utero causes a typical vaginal adenosis and some form of malignancy of the lower genital tract [7]. DES causes changes in expression of Wnt 7A, Hoxa 10 and Hoxa 11 genes, which are involved in tissue patterning of the genital tract. Hence altered uterine morphogenesis occurs with DES [8, 9, 10]. DES-induced developmental programming requires Estrogen Receptors (ER), suggesting that this signaling is important to establish developmental programming [11]. DES- exposed daughters have abnormal vaginal adenosis. Vaginal adenosis was also found in 80% of the stillborns & neonates exposed in-utero to DES. Endometriosis also requires special mention. The evidence is overwhelming in adult laboratory animals, that endometriosis can be promoted by many OrganoChlorines (OCs). Dioxin (TCDD), Methoxychlor and DDT, polychlorinated biphenyls are examples of OCs. Data linking OC exposure and endometriosis in adults women are equivocal, but DES to endometriosis are compelling. Limited sample size and confounding variables, are the JKIMSU, Vol. 1, No. 1, Jan-June 2012 ã Journal of Krishna Institute of Medical Sciences University weaknesses of observational epidemiologic studies.

Lifestyle affects fertility to a great extent. Smoking, consuming alcohol, the use of recreational drugs, so also unbalanced diet, over or under nutrition, all influence fertility. The former three affect sperm and egg qualities, as well as the reproductive process (due to presence of cadmium and cotinine). Both underweight and overweight women suffer from hormonal dysfunctions, hypertension, Recurrent Spontaneous Abortions (RSAs), Polycystic Ovarian Syndromes (PCOs) and Diabetes Mellitus (DM).

Infertility per se can cause psychological upset. It has been observed that 40% of infertile women meet the criteria of psychiatric disorders, as compared to 3% in community samples. Infertility along with the stress of treatment procedure can cause disturbed relationship with partners, family and friends, and also with the God. There may be disturbed sex life due to loss of interest. These can lead to severe financial insecurities as well as poor performance in job.

Stress itself is another factor for lowering the success rate in infertility treatment. More ovulatory dysfunction (PCO), tubal dysfunction, impaired spontaneousity about the attempt of pregnancy can happen due to stress. Stressed individuals have less sexual arousal, and ultimately end up in treatment dropout. It has been suggested that psychological stress exerts its effect through a reduction of pulsation frequency in Gonadotropin- Releasing Hormone (GnRH) release [12]. Stress can impair not only spontaneous reproduction procedures but also the reproductive technologies. It has been documented that in In-Vitro-Fertilization (IVF) programme, less number of oocytes are obtained from women under stress. They also produce diminished number of fertilized eggs along with diminished pregnancy rates, live birth rates as well as low birth weights [13].

As medical personnel are attending the infertile population, an extensive search has been undertaken to find the way outs. Primarily, psychological support in organized forms is found to be offered to the population suffering from infertility. Counseling is to be offered to individuals or in groups. The induction of positive approach, relaxation exercises, weight reduction, combined approach to family making are to be discussed. The development of couple communication, use of humour to reduce stress and goal setting are also important steps.

Psychological support in the infertility clinic is offered in an informal way. Easy and relaxed environment in the infertility clinic along with friendly behaviour from all the clinic staffs are encouraging. Help is given in decision-making. All the information is made available through website as well as discussion, and answers are provided to all questions. All telephone calls are attended with care and if necessary, counseling over the telephone is also offered. There should always be approach of tender loving care.

One should offer counseling in the following ideas in mind and try to convey many examples. Infertility is not a disease and it requires more supportive treatment. One should follow relaxed approach and try to be more of a friend and a guide than a doctor or a nurse. One should try to create confidence of the affected couple on the treating team as well as on themselves (self-confidence) and allay apprehensions about the treatment procedures.

One should convey to the infertile couple that pregnancy is a natural process, and the aim of the treatment should be to create an environment conducive for pregnancy to occur. One should not be crazy about pregnancy and let it happen itself naturally. Discussing personal experiences and informing case histories of the successful couples in the form of story telling also helps to build the confidence.

Induction of positive approach is another way of psychological supportive approach. Getting up early in the morning and doing some light exercises helps a lot. Avoidance of watching tele-serials showing family complications, rather seeing light entertainment shows or animal world cheers up the mind. The couples should avoid discussing treatment details with everyone, and avoid involving senior members of the family in decision-making. The couples should start preparing themselves to become true parents.

Setting up a goal is another important step. This means discussion regarding acceptance of the treatment procedures and how long the treatment procedure should be continued. A thorough information about the treatment modalities are to be provided, along with the standard outcome and success rates. The couples should understand the reasons for their own infertility and its expected outcome. Upto what level and how long the treatment may be accepted, are to be determined. The decision regarding alternative ways like adoption, doner oocyte programmes or third party reproduction (surrogacy) are to be discussed and determined.

Conclusion:

In conclusion, we should think about the ways to overcome the ill-effects of environment on infertility. Following may be some wayouts. The avoidance of stress, listening to music, more engagements with different jobs, like computer works, creative writing, distance and informal educations, community work, working with NGOs may help to elevate the confidence level. Help from the supportive groups may be of use. Less use of cosmetics and preserved foods may be helpful for future. Lifestyle modification, exercise, healthy food and drinks and avoidance to drugs should be practiced. Eating more organic food materials and creating a pleasant environment at home are very helpful. The stress of workplace should not be brought back to home. The treatment of infertility is a long war, which requires patience and perseverance to win over.

References:

1. Bell, E. M., Hertz-Picciotto, I., and Beaumont, J. J., ‘Fetal Deaths Linked to Living Close to Agricultural Pesticide Use During Weeks 3-8 of Pregnancy’,  http://www. chem-tox. com.pesticides (original source: Epidemiology, 12(2), March 2001); accessed: 16 July 2008.
2. Bell E, M., Pesticide Exposure Increases Miscarriage Risk; Epidemiology, March 2001.
3. Fimbrial pathology like fimbrial eversion, fimbrial agglutination or combination of both (11%).
4. Peritubal adhesion causing problem in tubal mobility and adhesions in the POD causing hindrance to reservoir function and egg pickup (4%).
5. Cornual or terminal tubal block developed in between the … Lap (3%).
6. Pedunculated fimbrial cysts, which can block the fimbrial opening of respective fallopian tube like a ball valve causing temporary tubal block (6%).              

Combination of above pathologies (44%) was most common.

The tubal kinks which were formed by serosa to serosal adhesion and thereby shortening of the effective tubal length were corrected by a simple procedure called Squeezing, Manipulation and hydrotubation (SMH) technique. For this procedure special tubal forceps were introduced (own design) through a 5mm port. This forceps is a modification of tube holding forceps where serrations in the inner surface were absent. These plane holding surfaces of forceps blades help in milking the tubal walls without causing injury. The forceps' broke the serosa to serosal adhesions thereby relieving the tubal kinks. Tubes were then milked from cornu to the fimbriae. As a result any sludge inside the tube was removed. The tubes got back their normal length. Hydrotubation with dye helped to wash out the remains and the tubes were opened when free spill occurred. Formation of C tube due to shortening of infundibulopelvic ligament was another difficult problem.  Attempt to lengthen the IP ligament by stretching was not always successful. The pulled up tubes failed to pick the released egg from the POD. In this situation inducing multiple ovulations might be helpful as the egg may float on excess amount of fluid in the pelvis and thereby might reach abdominal ostium passively of the tube. Fimbrial pathologies were corrected by fimbriolysis and fimbrial combing. Everted fimbriae due to mild grade PID were released by combing with palpating rod against the lateral pelvic wall. In other cases where thick membranous adhesions ran from fimbriae to ampulla they were cut with endoscopic scissors. The everted fimbriae, which were mostly formed by chemical irritation due to endometriotic blood, fimbriolysis with squeezing and milking was found to be helpful. In some irreversible evertions cutting the circular band with scissors or diathermy hook became very useful. Sometimes ostial dilatation by endoscopic forceps (Merryland) was necessary.

Peritubal adhesions needed use of multiple instruments to stretch the tube on one side and adherent structure on the other. The adhesion bands or membranes were then separated either by blunt dissection with the palpating rod or by sharp dissection with endoscopic  scissors. Any bleeding was coagulated by bipolar diathermy. Any peritubal adhesion with intestine was dealt with taking precaution not to injure intestine. If tubal serosa was adherent to the colon, intestines or lateral pelvic wall vessels the surgical approach should be more cautious and less heroic. Bleeding from that area might need a laparotomy. In these situations making the tissue wet by washing with irrigating solution or a hydrodissection was found to be very rewarding. Adhesions in the pouch of Douglus (POD) observed carefully. Filmsy adhesions were either excised when they were avascular or divided with diathermy hook. Restoration of POD completely or at least partially raised the success rate. Any maneouver that might injure rectum were avoided.
In case of cornual block, cornual massage with palpating rod or squeezing with special forceps might open the tubes on many occasions. A push and pull technique of hydrotubation along with squeezing and milking with tubal forceps and palpating rod might help in less organized block. In certain situations hysteroscopic division of adhesion relieved the block. Hysteroscopic tubal catheterization and use of balloon was not always rewarding. In certain situations when tubal fimbriae and/or ampulla was adherent to pelvic floor if simple attempt in separating failed not much of attempt was made as this is the dependent part where egg would come with follicular fluid and in close proximity to the fimbriae lying in the POD. Minimal hydrosalpinx should not be considered as hopeless. In certain situations opening the fimbriae saved the endosalpingeal damage. In case of healthy fimbriae with block, making a neoostium at close proximity to fimbriae sometimes yielded some results. In irreversible tubal damage where tubal blocks could not be relieved or there were major hydrosalpinx the outcome was hopeless. These are the cases, which should be listed for IVF and ET. Pedunculated fimbrial cysts are of special mention. It is difficult to diagnose them in usual tubal pretency tests as tubes were always patent. The alternate contraction of circular & longitudonal muscle of tubal wall created a negative pressure inside the fallopian tube which sucked the oocyte along with follicular fluid towards abdominal ostium. The pedunculated fimbrial cyst floated in follicular fluid might be drawn towards the abdominal ostium of fallopian tube and might block that tubal opening temporarily hindering egg pickup. Tubal cysts were easily excised using diathermy or scissors. In extremely small number of cases two conditions were noticed, one being tubal hump due to periampullary fat deposition and other being TIPS (Tube in pocket state). In 7 out of 846 cases, prominent fatty deposition over ampulla which extended upto infundibulopelvic ligament in 2 of them were noticed. These were named tubal humps. This condition impaired tubal mobility probably due to weight. Simple diathermy at 2 – 3 positions over the humps cleared fat deposition as it were observed during subsequent caesarean sections. In a small number (only eight) of cases the ampullary fimbrial end of the tube either unilaterally or bilaterally might be placed in peritoneal pockets hindering their mobility & egg pickup. The pocket developed either by formation of raised peritubal folds over uterosacral ligament or ureter which divided POD into compartments.

Sometimes pockets were formed due to peritoneal deficiency & pseudomembrane formation.  These result from mild to moderate endometriosis. This condition is called tube in a pocket state or (TIPS). The incidence of above two conditions was so small in this large series that they were not included in classification of minor tubal defects. Tubo Ovarian relation is very important for conception to occur. It is observed that tubo-ovarian (TO) relation might remain disturbed causing infertility. The position of the fallopian tube, particularly in ampulla fimbrial end might remain in following relation to the ovaries. The fimbrial end of the Fallopian tube should lie medial to the ipsilateral ovary and reach the POD. Depending on tubal relation to the ovary following grades could be thought of:

TOR 1 (Tubo ovarian relation 1) where ampullofimbrial end lying lateral to ovary.
TOR II tubal fimbriae lying on superolateral end of the ovaries.
TOR III fimbrial end lying on medial surface of the ovary
TOR IV where fimbrial end reaching the floor of POD nicely, lying medial to the ovary.
TOR IV position is most favorable position for pregnancy to occur.

Post surgical follow up

The follow up treatment consisted of postoperative hydrotubation with normal saline mixed with non-specific anti-inflammatory agents like placental extract supported by oral antibiotics once a month for 3months. In cases of endometriosis post operative treatment with Danazole or Progestins was essential to control the basic pathology. When the pathology appeared to be inflammatory oral antibiotic selection was very important. Test for Chlamydia trachomatis is very costly in this country. So in suspected cases we used suitable multiple antibiotics against Chlamydia usually sequentially for 7 days – 3weeks.

Discussion

The fallopian tube has four functions in achieving pregnancy. It must be open with intact endosalpinx. It must have adequate length to reach the pelvic floor. It has to be mobile to reach the site of released egg and to create a negative pressure in itself. The fimbriae should be normal and free, to direct the egg towards the tubal ostium. The surgical approach should be directed to get all the tubal functions back in a damaged or diseased tube. It has been observed from the present study that certain simple measures can alleviate tubal pathology to great extent and restore all the aforesaid functions. The common causes of tubal pathology now- a-days are PID (Pelvic Inflammation) mostly due to low grade infection by Chlamydia3, Streptococcus or E. coli. On many occasions tubal kinks and thereby shortening of the effective tubal length, can happen due to chemical inflammation arising form endometriotic blood in the pelvis in which tubes float following menstruation. These tubal kinks look like below of piano-accordian and cause shortening of the effective length of the fallopian tubes. As a result tubal fimbriae fail to reach the pelvic floor and thereby fail to achieve egg pick up. Sometimes tubal defects are results of post abortal or puerperal infections as it happens in secondary infertility4. Majority of tubal blocks are of mild form and simple SMH may open the tubes easily. Postoperative hydrotubation further maintains the patency of the tubes. Peritubal adhesiolysis should be performed with great caution as multiple organs including major blood vessels may be involved. Fimbrial pathology is another worth mentioning in group of tubal defects which can arise from mild or minimal endometriosis or some other mild from pelvic infection. The minimal tubal defects are mostly associated with endometriosis. This is our observation that adherent fimbriae on many occasions cause infertility due to poor egg pick up even in cases of anatomically patent tubes.  If the fimbriae are not inspected properly in video monitor under magnified view the defects pass unnoticed. These cases are regarded as unexplained infertility. Lyses are also very important to get back mobility of fallopian tubes. Peritubal adhesion needs freeing of tubes for proper mobility and function. It is observed that when a tubal block is due to fibrosis the endosalpingeal damages is substantial. Tubal patency depends on endosalpingeal integrity. Major endosalpingeal damage results in irreversible tubal block or hydrosalpinx. Minor endosalpingeal damages are self-repaired for which usually 6 months is necessary. Hence it takes about 6 months to one year in achieving a pregnancy in majority of patients following tubolysis. After adhesiolysis bleeding from tubal serosa should be dealt with caution. In most of the cases bleeding stops on pressure or on its own. If diathermy is necessary bipolar is a better choice, as there is minimal scattering of coagulated current. Any blood clot or carbon particle produced as a result should be washed out carefully to prevent readhesion. Infact, minor tubal defects are usually being stamped as unexplained infertility, atone said observation suggests. Tubo-ovarian relation is to be evaluated with great care and corrective measures are to be undertaken. TOR I position is mostly associated with C tubes. TOR IV position is most favorable position for pregnancy to occur.

Result Analysis

During last 10 years, 846 cases of primarily unexplained infertility along with some cases of anovulatory infertilities not conceiving even after ovulation correction were subjected to laparoscopic evaluation After corrective measures 209 (about 25%) cases conceived either normally or by IUI, otherwise called non ART way. Out of remaining cases IVF and ET were performed in 201 cases which subsequently yielded pregnancy in 53 cases (about 26%). This is a 3 cycles cumulative data for IVF and 6 – 12 cycles attempts for non ART pregnancies. Forty nine cases who had failure of one to three IVF attempts previously were subjected to laparoscopy as they were unwilling to go for further IVF procedure. Thirty seven of them had minor tubal defects and after correction nine of them conceived in non ART way yielded a success rate of 24.9%. Forty eight cases of major tubal defects were subjected to laparoscopic corrective procedures yielding a non ART pregnancy in 3 cases only (6.5%). Forty cases amongst them had IVF treatment when 9 cases conceived following IVF (22.5%). It has been observed that following laparoscopic corrective surgery for minor tubal defects most of the pregnancies occur between 6months to one year after attempts of pregnancy is undertaken. The pregnancy rate drops down significantly after one year of attempts and becomes negligible after one and half years following corrective laparoscopy 5. This is comparable to results obtained after laparoscopic ovarian cystectomy in infertile women in same centre 8. Incidentally, the ectopic pregnancy rate is similar to that of non-tubal infertility group in minor tubal defects, indicating the amount of endosalpingeal damage in this group. 

Conclusion:

It appears from the present study that half of the cases of so called unexplained infertility are due to minor tubal defects which pass unnoticed if not observed with great care during laparoscopy. The main cause of such tubal defects may be due to sub clinical PID or mild grade endometriosis. There may be altered tubo ovarian relation due to same aeteology and so also disturbed function of POD. The main object of the corrective procedures is to get a freely mobile Fallopian tube having proper length and fimbrial function alongwith satisfactory tubo ovarian relation. Recovery of POD is also another important aim such that proper egg pickup can take place. The pregnancy outcome following the corrective procedures in cases of minor tubal defects are also comparable to that of IVF success rates.

Reference:

1. Alice D Domar. The mind/body connection In Bayer Steven R, Alper Michael M, Penzias Alan s eds. The Boston IVF handbook of Infertility Informa UK 2007: 177-185.
2. Chatterjee S and Chakravarty S, Screening of endometriosis at an early stage: A simple clinical approach. J. Ind. Med. Assocn, 2000: 98: 387-393.
3. Giudice Linda C.; Environmental Contaminants and Female Reproductive Capacity; July 15, 2008.
4. Cohn BA, Wolff MS, Cirillo PM, Sholtz RI. DDT and Breast Cancer in Young Women: New Data on the Significance of Age at Exposure; Environ Health Perspect Oct 2007; 115(10): 1406–1414.
5. Bobak M.; Outdoor air pollution, low birth weight, and prematurity; Environ Health Perspect Feb 2000; 108(2):173-6.
6. Jensen Kold Tina, Skakkebaek NE; Environment & Reproduction; Opening Lectures; 9th Congress of the European Society of Gynecology Book of Abstracts; Copenhagen, Denmark, 8-11 September, 2011: 5.
7. DES History (Internet Version dated October 24, 2011); Centers for Disease Control and Prevention (CDC).
8. Ma L, Benson GV, Lim H, Dey SK, Maas RL.; Abdominal B (AbdB) Hoxa genes: regulation in adult uterus by estrogen and progesterone and repression in müllerian duct by the synthetic estrogen diethylstilbestrol (DES); Dev Biol. 1998 May 15;197(2):141-54
9. Miller C., Sassoon D.A.; Wnt-7a maintains appropriate uterine patterning during the development of the mouse female reproductive tract; Development; August 15, 1998; 125, 3201-3211
10. Block Karen, Kardana Andrew, Igarashi Peter, Taylor Hugh S.; In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing mu¨llerian system; The FASEB Journal; June 2000; Vol. 14, 1101-1108.
11. Couse JF, Dixon D, Yates M, Moore AB, Ma L, Maas R, Korach KS. Estrogen receptor-alpha knockout mice exhibit resistance to the developmental effects of neonatal diethylstilbestrol exposure on the female reproductive tract. Dev Biol Oct 15 2001. 238(2):224-38.
12. Kiumars P, Talaeerad Z, Mohammadi K, Nazari M, Bigdeli H, Haddadmanesh H, Zarei K. Psychological stress causes relative infertility through direct change in the frequency pattern of GnRH release from the hypothalamus; Opening Lectures. 9th Congress of the European Society of Gynecology Book of Abstracts. Copenhagen, Denmark, 8-11 September, 2011: 241
13. Nermin Gurhan, Aygül Akyüz, Atici D, Kisa S. Association of depression and anxiety with oocyte and sperm numbers and pregnancy outcomes during In Vitro Fertilization treatment (Internet Version). Psychological Reports. Volume 104: 796-806.

Click here to download the report in pdf format