Infertility: Etiology And Evaluation

Lisa A. Farah, M.D.
Lisa A. Farah, M.D. is a reproductive endocrinology and infertility specialist
with North Florida Gynecologic Specialists in Jacksonville.

Introduction

The inability of a sexually active, noncontracepting couple to achieve a conception within one year constitutes infertility. Primary infertility occurs in women who have never conceived. Secondary infertility occurs in women with a previous conception. Infertility affects approximately 15% of couples, and approximately 1.3 million women.1 Although the prevalence of infertility appears to be stable, there is an apparent increase in the number of referrals to specialty clinics. Between 1982 and 1988, the percentage of women with impaired fecundity was stable; however, the use of infertility services and the number of physicians providing infertility treatment increased.2 More women with primary rather than secondary infertility seek medical advice. Approximately 4% of infertile women will never have a child, and another 4 to 6% will not achieve a subsequent live birth.3 The psychological and financial burdens that this diagnosis places on couples can be devastating. Expenditures for infertility treatment in the United States are estimated to be approximately one billion dollars per year.

The etiologies of infertility include ovulatory dysfunction, tubal/pelvic pathology, male factor, other factors and unexplained infertility. Anovulation is the underlying cause of infertility in approximately 30% of women, uterine or tubal factors are responsible for another 20%, a male factor is identified in approximately 40% of cases, approximately 5% of cases anatomic abnormalities, cervical factors, or immunological problems are identified and in the remainder of cases no specific abnormality is identified (unexplained infertility).4 In approximately 20% of cases, an abnormality is identified in both partners.5

Ovulatory Dysfunction

Disorders of ovulation include advanced maternal age, premature ovarian failure, the polycystic ovary syndrome, and other androgenic disorders such as nonclassic adrenal hyperplasia, hypothalamic anovulation, thyroid dysfunction, and hyperprolactinernia.

These patients can be divided into three categories based on their hormonal milieu. One includes patients with hypoestrogenic hypogonadism. These patients have estrogen levels in the postmenopausal range, with normal to low follicle stimulating hormone (FSH) levels and normal prolactin (PRL) levels. This includes patients with hypothalamic amenorrhea, anorexia nervosa or exercise/weight loss related amenorrhea, and Kallmann's syndrome. The second group includes patients with normal estrogen levels and normal FSH levels. Polycystic ovary syndrome is included in this group. Finally, the third group exhibits hypergonadotropic hypogonadism. These patients have elevated FSH and postmenopausal estrogen levels, including patients with premature ovarian failure.

Age And Infertility

The oocyte arises in the embryonic period. The maximal number of oocytes is reached by 1620 weeks of gestation (approximately 67 million). The number of oocytes begins to decrease from the maximal number at 1620 weeks to 700,000 at birth to 300,000 at puberty.6 During any one month, an entire cohort of follicles (1015) is recruited, yet only one dominant follicle is selected to ovulate. Atresia of the oocytes is not interrupted by pregnancy, ovulation, or periods of anovulation. A complete discussion of age and infertility can be found in a separate article in this same issue ("Biological Clock: Fact or Fiction").

Premature Ovarian Failure

Premature ovarian failure (POF) is diagnosed when amenorrhea coexists with elevated gonadotropins in a woman who is < 35 years of age. If POF occurs in a patient who is < 30, a karyotype is recommended. POF has several etiologies, including iatrogenic (radiation therapy, chemotherapy, surgery), chromosomal abnormalities (e.g., Turner's syndrome, deletions of the X chromosome), autoimmune disorders such as hypothyroidism (most common), myasthenia gravis, and metabolic disorders such as galactosemia, although the mechanism in the latter case remains to be elucidated.

Polycystic Ovarian Syndrome

The association between the pathologic finding of obesity, abnormal uterine bleeding, and hirsutism was first described by Stein and Leventhal in 1935.7 Since that original report, the complexities of the syndrome have continued to unravel. The polycystic ovary syndrome (PCOS) is the most common ovarian etiology of anovulation. It is best known as a syndrome of chronic anovulation and hyperandrogenism. It is one of the most common causes of oligoovulatory infertility and typically affects 5% of reproductive aged females. It is characterized by hirsutism, obesity, elevated androgens, insulin resistance and infertility.

Not only does PCOS have implications for female fertility and a sense of wellbeing, it is also associated with many adverse health outcomes, such as obesity, increased risk of cardiovascular disease (CVD), noninsulin dependent diabetes mellitus, and endometrial carcinoma. Patients exhibit male patterns of lipoprotein concentrations. Perturbations in cholesterol and triglyceride metabolism can lead to premature CVD. Conway, et al compared lean and obese women with PCOS and normal women. They reported that lean and obese women with PCOS had hyperinsulinemia as well as reduced high density lipoproteins. The obese PCOS patients were also found to have higher systolic blood pressures, serum triglycerides and plasma glucose concentrations than lean PCOS patients and controls. They concluded that PCOS patients with hyperinsulinemia are at increased risk of developing CVD.8 Therefore, it is important to recognize this potential for serious metabolic dysfunction and to screen for lipid abnormalities and insulin resistance.

Patients with PCOS usually present with menstrual disturbances (oligomenorrhea or dysfunctional uterine bleeding). This symptom is often accompanied by increased male pattern hair growth (hirsutism), acne, alopecia, obesity, or infertility. These patients often provide a history of premature adrenarche, peripubertal obesity, and depending on the degree of obesity, either early or delayed menarche (with morbidly obese patients experiencing delayed menarche and possibly even primary amenorrhea).

Thyroid Dysfunction

Both hyperthyroidism and hypothyroidism may result in menstrual disturbances secondary to anovulation. The mechanism for menstrual dysfunction appears to be alterations in the metabolism and interconversion of androgens and estrogens. The degree of disturbance varies from amenorrhea to dysfunctional uterine bleeding. Except for severe cases, most hyperthyroid patients remain ovulatory and fertile. Therefore, pregnancy should be considered in the amenorrheic hyperthyroid patient.9

In hypothyroidism, the result of the hormonal alterations is an increase in estrogens which may lead to inappropriate gonadotropin secretion and anovulation. In hypothyroidism, the serum PRL level may also be increased and galactorrhea may occur.9 This may be due to the fact that thyrotropin releasing hormone (TRH) may increase the secretion of both thyroid stimulating hormone (TSH) and PRL. An alternative explanation is that there is diminished hypothalamic dopamine turnover.9 These disturbances (i.e. hyperprolactinemia and galactorrhea) will resolve with thyroxine treatment.10

Hyperprolactinemia

Prolactin (PRL) is secreted primarily by the pituitary lactotrophs from the posterolateral aspects of the adenohypophysis, the most common location of prolactinomas. Prolactin is a peptide hormone and is structurally similar to somatomammotropic hormones, including growth hormone and human placental lactogen. Prolactin release is stimulated by a variety of substances, such as TRH, GnRH and oxytocin. The anovulatory mechanism in hyperprolactin-emic amenorrhea is thought to be inhibition of GnRH pulsatility by elevated PRL levels.11 Hyperprolactinemia leads to a failure of the positive feedback response of gonadotropin secretion induced by estrogen.12 Therefore, patients exhibit low levels of LH and FSH.

Most laboratories report an upper range of normal of 20 to 30 ng/mI for prolactin levels. A single elevated prolactin level should be repeated as prolactin is a dynamic hormone. Patients with prolactin levels greater than 100 ng/ml should undergo pituitary imaging (magnetic resonance imaging or computed tomography). A TSH level should be obtained to rule out hypothyroidism. Imaging could be obtained at lower levels as it was found that levels greater than 50 ng/ml were associated with a 20% frequency; 100 ng/ml, a 50% frequency; and greater than 100 ng/ml, a nearly 100% frequency of a pituitary tumor.13

Prolactinomas are categorized as microadenomas (< 1 cm) or macroadenomas (> 1 cm). Microadenomas can be managed expectantly. Symptomatic patients and patients with macroadenomas can be treated medically or surgically. The majority of patients respond to medical treatment. Most infertile patients with elevated prolactin require therapy.

Tubal And Pelvic Pathology

In industrialized countries, the annual incidence of pelvic inflammatory disease (PID) in women aged 15 to 39 appears to be 10 to 13 per 1,000 women, with a peak incidence of approximately 20 per 1,000 women in the age group 20 to 24 years.14 The incidence of PID is correlated strongly with the prevalence of sexually transmitted diseases (STD's), namely Neisseria gonorrhea and Chlamydia trachomatis. The risk of acquiring an STD increases with the number of sexual partners of either the male or the female. In addition, associated risk factors include early age at first coitus, single marital status and history of illicit drug use. Westrom's investigations have shown that women who have had acute PID are at significantly increased risk to develop tubal factor infertility or ectopic pregnancy (6- to 10-fold increased risk of ectopic).14 Westrom also reported on the examination of 415 women 9.5 years after initial treatment for PID. The proportion of infertile patients increased with the number of infections: 12.8% after one infection, 35.5% after two infections, and 75% after three or more. Infertility from one episode increased with the severity of the infection and with the age of the patient.15 In addition to tubal factor infertility and the risk of ectopic pregnancy, these patients suffer the sequelae of pelvic infection including pelvic adhesive disease and chronic pelvic pain.

The use of intrauterine devices (IUD) is associated with an increased risk of PID and of infertility. Gump, et al noted that both the IUD and chlamydial antibody were associated with an approximately threefold increased risk for previous PID. They also reported that approximately 50% of the patients with evidence of previous PID never recalled a history of diagnosis or treatment for PID.16

Endometriosis is defined as the presence of endometrial glands and stroma in an ectopic location. In 1927, Sampson first described retrograde menstrual flow through the fallopian tubes as the probable cause of endometriosis.17 Endometriosis in areas distant to the uterus and pelvic organs can be secondary to lymphatic or hematogenous spread. An example of this is a patient who experiences catamenial hemoptysis secondary to pulmonary endometrial implants. Another theory of the development of endometriosis is that of coelomic transformation. Reports supporting this theory include the finding of endometriosis in men receiving high dose estrogen therapy and endometriosis in a prepubertal girl.

Endometriosis is reported in a significantly higher percentage of infertile than fertile patients. Verkauf compared 143 women undergoing diagnostic laparoscopy for infertility with 251 fertile women undergoing laparoscopic tubal ligation. Endometriosis was found in 38.5% of infertile patients versus 5.2% of the fertile women.18 The mechanisms whereby endometriosis leads to infertility are varied. Adhesions of the fallopian tubes and ovaries could cause mechanical interference in ovum pickup. Severe endometriosis can lead to complete tubal obstruction. There have been reports of increased prostaglandins in the peritoneal fluid of patients with endometriosis. This could interfere with tubal mobility or folliculogenesis and corpus luteum function. In addition, an increase in the number of peritoneal macrophages and cytokines has been reported in women with endometriosis. These macrophages could lead to phagocytosis of the sperm.

In evaluating a patient for the possibility of tubal damage secondary to pelvic infection or endometriosis, it is important to elicit a sexual history, to inquire about previous abdominal or pelvic surgery or history of pelvic infection, and to investigate prior methods used for contraception. Infertile women being evaluated for the possible presence of endometriosis should be questioned about the presence of pelvic pain and dysmenorrhea. A history of late onset dysmenorrhea is consistent with endometriosis (the cumulative effect of many years of retrograde menstrual flow). The degree of pelvic pain is unrelated to the severity of disease, as patients with extensive endometriosis can be asymptomatic and mild endometriosis can cause debilitating pain. Patients may have symptoms reflective of bowel, bladder or ureteral involvement of endometriosis. Patients with bowel involvement may report a history of hematochezia or dyschezia.

Lifestyle Factors

Cigarette Smoking

Approximately 30% of women in the United States smoke and the incidence of smoking in young women appears to be increasing. As a result of this increase, women in developed countries are more likely to die from lung cancer than breast cancer.19 Cigarette smoke and its constituents as well as nicotine appear to have adverse effects on many biological mechanisms required for successful reproduction in both humans and experimental animals.20 Cigarette smoking appears to decrease fertility in women and demonstrates a doseresponse effect. Women who smoke also appear to experience lower circulating levels of estrogen and an earlier age at spontaneous menopause. This may also be due to accelerated oocyte depletion, which has been observed in rodents exposed to benzo(a)pyrene.20 It has also been demonstrated that smoking increases the time to conception and spontaneous abortion risk.21 Smoking also decreases sperm quantity. The effect of passive smoke on male and female reproduction is unknown.

The effects of cigarette smoking are difficult to assess epidemiologically secondary to the presence of many confounding variables such as lower socioeconomic status, and alcohol and drug use. However, Phipps et al reported on the association between smoking and cervical and tubal factor infertility. They included potential confounding variables in a multivariate model and noted that the association between smoking and tubal disease or cervical factor persisted.22

Alcohol, Caffeine And Illicit Drug Use

Although moderate alcohol consumption does not appear to decrease fertility, heavy alcohol consumption is known to have an adverse effect on reproduction. The adverse fetal effects of alcohol are also well known. Wilcox, et al reported that married women attempting to conceive and found that those who drank more than four cups of coffee per day had only an 81% chance of becoming pregnant per cycle compared to non-coffee drinkers.23 Grodstein, et al also reported that the consumption of more than seven grams of caffeine per month increased the risk of tubal factor, endometriosis related, and cervical factor infertility.24 Mueller et al reported that marijuana increased the risk of ovulatory infertility, especially use within the year preceding attempted pregnancy.25 The mechanism of anovulation appears to be suppression of gonadotropin releasing hormone (GnRH) and pituitary release of gonadotropins.

Exercise And Weight Loss

Hypothalamic anovulation is secondary to an abnormal pulsatile release of GnRH. 26 Many lifestyle factors, such as stress, depression, exercise, and dieting have been shown to lead to hypothalamic anovulation. It is well known that a critical fat mass is necessary in order to initiate ovulatory cycles.27 In a society that is obsessed with body image and appearance, many women have adapted rigid exercise programs for themselves and thus, have an altered height-to-weight ratio. This is more common in women who engage in strenuous exercise. It is necessary to elicit the type, duration, and intensity of exercise when taking the history. Another circumstance in which anovulation may be secondary to weight loss and subsequent hypogonadotropic hypogonadism is in women who suffer from eating disorders. This is usually a diagnosis that is made in the second decade of life, and rarely after the mid-20's.

Male Factor

In 40% of patients, the etiology of infertility is found to be the male partner. The underlying causes include lifestyle factors (i.e., cigarette smoking, alcoholism, heat from hot tubs), failure of ejaculation, retrograde ejaculation, infection, malignancy, varicocele, immunological factors, hypogonadotropic hypogonadism (Kallmann's syndrome), iatrogenic (i.e., medications), or previous vasectomy. It is important to elicit information regarding previously fathered pregnancies, medical history including medication usage (including over the counter medications), trauma, history of mumps orchiitis, environmental factors and heat exposure.

Men with a spinal cord injury, diabetic neuropathy, or who have undergone a retroperitoneal lymph node dissection may suffer from failure of ejaculation or from retrograde ejaculation. These men can be treated with external vibratory massage, oral medications, electroejaculation, or intraoperative recovery of sperm from the vas deferens or epididymis. Medical treatments include alphaadrenergic agonists, such as ephedrine sulfate, pseudoephedrine hydrochloride and ephedrine hydrochloride. Electroejaculation is very useful in patients with spinal cord injury, as no anesthesia is required. In the case of retrograde ejaculation, if medical therapy fails, fluid intake can be adjusted so that the urine is isotonic and sodium bicarbonate can be given to alkalinize the sample. The sperm can then be recovered either by having the man void or through catheterization. Although infection is rarely a cause of male infertility, any documented infection occurring in the female partner should also be treated in the male. This is especially important in that some have reported the involvement of inflammatory cytokines and cytokinesoluble receptors in the regulation of the male reproductive system and sperm function.28

Many patients with testicular cancer demonstrate impaired fertility before therapy. In some, this resolves with treatment; however, in others treatment with cytotoxic chemotherapy, namely cisplatin, worsens the prognosis. The impairment in spermatogenesis is considered irreversible with a cumulative dose of cisplatin of > 400 mg/m2.29

Medications such as antibiotics and antihypertensives can interfere with spermatogenesis. Cimetidine, spironolactone, nitrofurans, sulfasalazine, erythromycin, tetracyclines, Azulfidine®, Procardia®, and anabolic steroids decrease the quantity and quality of sperm. Ejaculatory dysfunction can be caused by alphaantagonists such as phentolamine, methyldopa, and reserpine. Betablockers, commonly used to treat hypertension, can cause impotence.

Previous vasectomy is a common reason for presentation for infertility treatment. The chances of success increase with decreased time from initial surgery. In one study of vasectomy reversal, the pregnancy rate for the partners of patients who had a vasectomy less than three years earlier was 76%, versus 30% for the partners of those who had a vasectomy 15 years before vasovasostomy.30

Heavy alcohol consumption (abuse) is known to decrease sperm counts and testosterone levels in men. This may lead to erectile dysfunction. In addition, there have been reports of decreased sperm concentration in men who smoke, as well as abnormal morphology and decreased numbers of motile sperm.31 However, a recent Swedish study did not corroborate these findings.32

Unexplained Infertility

If the entire workup for infertility is found to be normal, the couple is said to have unexplained infertility, which occurs in approximately 10% of cases. It should be realized that while the term "unexplained infertility" is used to describe couples who have undergone no more than 8-9 basic tests with negative results, reproduction involves an unknown number of processes that could be dysfunctional.

Multifactor Infertility

While the causes of infertility are often times segregated for convenience of discussion, this is not the pattern found in clinical practice. It is quite common to have a situation where the husband's sperm count is adequate but decreased, the woman has subtle inconsistencies in ovulation, stage I-II endometriosis may be present, and a suboptimal postcoital test may be noted, at least in some cycles. Therefore, an infertility evaluation should be completed as rapidly as possible and attention turned to all problems, as a slight improvement in any one of the dysfunctional areas may result in pregnancy.

Evaluation Of Infertility

Patient Education

Education of the infertile couple is the cornerstone to the treatment of their problem. Most couples, despite being relatively well educated, have a rudimentary understanding of reproductive biology. The couple should be advised to have intercourse within the fertile zone (cycle days 1216), and should be informed that conception can occur with intercourse occurring as distant as five days prior to ovulation. Couples should be discouraged from using any form of artificial lubricants as all of these agents have a deleterious effect on sperm function and viability. Further, realistic goals should be set for the couple. They should be informed that conception usually occurs within 4-6 months and that no couple conceives at greater than about 25% per cycle. Couples should be encouraged to alter any unfavorable lifestyle practices that would decrease their chance of pregnancy, the woman should be started on prenatal vitamins with adequate folic acid content to reduce the risk of  neural tube defects. It should be mentioned that any couple expressing a concern over their reproductive potential deserves a basic infertility evaluation, despite a history of less than one year of attempting conception.

Progesterone Level

A midluteal progesterone level is useful in determining the occurrence of ovulation. This level should be drawn approximately 6 to 8 days prior to the onset of the expected menses. A level ³10 ng/ml is considered indicative of adequate ovulation, although a single low value does not exclude ovulation. It should be kept in mind that progesterone is secreted in a pulsatile fashion and that a single abnormal value should not be accepted as evidence of anovulation especially in light of a history suggestive of ovulatory cycles.33 The progesterone level can be used in conjunction with a midcycle ultrasound as combined indicators of adequate ovulation.

Endometrial Biopsy

In order to evaluate the adequacy of the luteal phase, an endometrial biopsy can be performed three days prior to the onset of expected menses. The biopsy can also be timed prospectively by using urinary LH kits and ultrasound to assess for the presence of a dominant follicle.

Luteal phase dysfunction is diagnosed if the histological findings lag behind the expected cycle duration by more than two days. It should be noted that endometrial biopsy is used less frequently with the advent of modern ultrasonography and other noninvasive tests.

Ultrasound Evaluation

Ultrasound evaluation in the periovulatory period can be performed in order to assess the development of a dominant follicle. A follicle reaches maturity and is prepared to ovulate when it becomes approximately 1.8 to 2.0 cm in size. The ultrasound is best timed by having the patient use home urinary LH kits. Follicular size can be correlated with the timing of an adequate LH pulse. The exam may be single or sequential.

Postcoital Test

The urinary LH kits can also be used to time the postcoital test (PCT). Once a patient detects a surge, she presents to the physician's office 24 hours later and approximately 2 to 6 hours after intercourse. At that time, a speculum exam is performed and cervical dilation, Spinnbarkeit and amount of the cervical mucus, and numbers of motile sperm per high power field (HPF) are assessed. Ideally, one would like to see a dilated cervix with abundant clear, watery mucus (with Spinnbarkeit measuring at least 8 to 10 cm), and at least 515 progressively motile sperm per HPF.

Semen Analysis

It is imperative to perform a semen analysis in all couples presenting for infertility evaluation, as in up to 40% of cases of infertility, a male factor is identified. The parameters examined include volume, total number of sperm, percent of motile sperm, and percent normal forms. Longitudinal analyses of semen from infertile men who subsequently established a pregnancy indicated that their motility was usually greater than or equal to 40% with grade 2.5 motility or better and the percentage of sperm with normal morphology was usually 60% or more.34 The World Health Organization suggests that a count of 20 x 106 sperm/cc is adequate for fertility although lower than most population normals. If an abnormal analysis is obtained it should be repeated in eight weeks as spermatogenesis takes ± 74 days to complete.

Hysterosalpingogram

Because tubal disease is responsible for approximately 20% of cases of infertility, the hysterosalpingogram (HSG) should be performed early in the workup of infertility. The HSG is useful in the evaluation of the endometrial cavity as well as the intraluminal environment of the fallopian tubes and tubal patency. However, the HSG is not usually useful in the diagnosis of pelvic pathology such as pelvic adhesive disease or endometriosis. The HSG is performed in the follicular phase of the menstrual cycle, soon after menses has ceased. This avoids reflux of menstrual blood into the peritoneal cavity and prevents performing the test in the luteal phase. An oil or waterbased contrast media is used. The study is performed under fluoroscopy. A followup xray may or may not be used.35

It is recommended that the patient's physician perform the exam with the radiologist. This aids the physician in interpreting the results more effectively. In addition, the obstetrician/gynecologist or reproductive endocrinologist can adapt their procedure to the findings on fluoroscopy. There is some data to support the fact that pregnancy rates are increased with oilbased contrast media.36

Laparoscopy

A laparoscopy is usually performed when intrapelvic pathology is suspected or at the end of an infertility workup. If there are any abnormalities on HSG which suggest intrauterine pathology, the laparoscopy can be performed in conjunction with a hysteroscopy. It is preferable to perform the laparoscopy in the follicular phase to avoid disrupting a possible early pregnancy. Laparoscopy is the standard for diagnosis of endometriosis and tubal disease. The HSG can only suggest pelvic pathology.

Conclusion

The evaluation of infertility requires a comprehensive approach to the couple as a unit. By the time that the couple seeks the consultation of a reproductive endocrinologist, they are oftentimes emotionally burdened. In addition to the psychological stress placed upon them, many patients find that their insurance policies oftentimes do not cover any infertility services, leaving them feeling abandoned.

Only in the states of Massachusetts, Illinois and Maryland are any mandates in place that assure infertile couples paid access to assisted reproductive technologies. In reality, these services could be furnished for as little as fifty cents per member per month, which is minuscule compared to other uncommonly used benefits such as rehabilitation services. These economic dilemmas often push couples to further delay childbearing, which results in an exponential fall in fecundity rates, and an exponential rise in both the rate of miscarriage and genetic anomalies in offspring. This unfortunate circle of events has dramatic negative impacts on the couples' private lives with divorce rates greatly exceeding those of the general population. Further, this has a direct effect on employers as unhappy couples tend to be less productive. It is an unfortunate social commentary, as given today's technology, virtually all couples willing to avail themselves to advanced therapy conceive.

REFERENCES

  1. Mosher W, Pratt W. Fecundity and infertility in the United States, 1965-88. Adv. Data. 1990;192:1-12.
  2. Stephen EH. Projections of impaired fecundity among women in the United States: 1995-2020. Fertil Steril. 1996; 66:205-9.
  3. Schmidt L, Munster K. Infertility, involuntary infecundity, and the seeking of medical advice in industrial countries. 1970-1992; a review of concepts, measurements and results. Hum Reprod. 1995; 10:1407-18.
  4. Blackwell RE. Clinical aspects of aging of the female reproductive system. In: Steinkampf MP. Infertility: Causes, diagnosis and treatment. In: Soules M (ed), Problems in Reproductive Endocrinology and Infertility, New York, NY, 1989.
  5. Rashef E, Daniel WW, Foster JC, Bradley EL, Blackwell RE, Younger JB. Accuracy of 1-hour vs. 24-hour follow-up films in hysterosalpingography. Fertil Steril. 1989; 52:753-55.
  6. Schiff I, Wilson Schneider EL (ed), The Aging Reproductive System, New York, NY Raven Press 1978;9-28.
  7. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol. 1935; 28:181-91.
  8. Conway GS, Agrawal R, Betteridge DJ, et al. Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol. 1992; 37(2):119-25.
  9. Thomas R, Reid RL. Thyroid disease and reproductive dysfunction: a review. Obstet Gynecol. 1987; 70:789-98.
  10. Edwards CRW, Forsyth IA, Besser GM. Amenorrhea, galactorrhea, and primary hypothyroidism with high circulating levels of prolactin. Br Med J. 1971;3:462-4.
  11. Yen SSC. Prolactin in human reproduction. In Yen & Jaffe (eds), Reproductive Endocrinology, WB Saunders, Philadelphia, 1991;357-88.
  12. Aono T, Miyake A, et al. Restoration of oestrogen positive feedback effect on LH release by bromocriptine in hyperprolactinemic patients with galactorrhea-amenorrhea. Acta Endocrin. 1979; 91(4):591-600.
  13. Plotsky PM, Neill JD. Interactions of dopamine and thyrotropin-releasing hormone in the regulation of prolactin release in lactating rats. Endocrinology. 1982; 111:168.
  14. Westrom L. Incidence, prevalence, and trends of acute pelvic inflammatory disease and its consequences in industrialized countries. Am J Obstet Gynecol. 1980; 138:880-92.
  15. Westrom L. Effect of acute pelvic inflammatory disease on fertility. Am J Obstet Gynecol. 1975;121:707-13.
  16. Gump DW, Gibson M, Askikaga T. Evidence of prior pelvic inflammatory disease and its relationship to Chlamydia trachomatis antibody and intrauterine contraceptive device use in infertile women. Am J Obstet Gynecol. 1983; (2)146:153-9.
  17. Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927; 14:422.
  18. Verkauf BS. Incidence, symptoms, and signs of endometriosis in fertile and infertile women. J Fla MA. 1987; 74(9):671-5.
  19. Department of Health and Human Services. The health consequences of smoking: cancer: a report of the Surgeon General. New York: American Cancer Society, 1993.
  20. Mattison DR. The effects of smoking on fertility form gametogenesis to implantation. Exp Research. 1982; 28:410-433.
  21. Hughes EG, Brennan BG. Does cigarette smoking impair natural or assisted fecundity? Fertil Steril. 1996; 66:679-89.
  22. Phipps WR, Cramer DW, Schiff I, et al. The association between smoking and female infertility as influenced by cause of the infertility. Fertil Steril. 1987; 48:377-82.
  23. Wilcox A. Weinberg C, Baird D. Caffeinated beverages and decreased fertility. Lancet. 1988; 24 (31):1453-6.
  24. Goldstein F, Goldman MB, Ryan L, et al. Relation of female infertility to consumption of caffeinated beverages. Am J Epidemiol. 1993: 117:1353-60.
  25. Mueller BA, Daling JR, Weiss NS, et al. Recreational drug use and the risk of primary infertility. Epidemiology. 1990;1:195-200.
  26. Yen SS, Rebar R, VandenBerg G, et al. Hypothalamic amenorrhea and hypogonadotropinism: Responses to synthetic LRF. J Clin Endocrin & Metab. 1973;36(5):11-6.
  27. Frisch RE. Body fat, menarche, and reproductive ability. Semin Reprod Endocrinol. 1985; 3:45.
  28. Huleihel M, Lunenfeld E, Levy A, et al. Distinct expression levels of cytokines and soluble cytokine receptors in seminal plasma of fertile and infertile men. Fertil Steril. 1996;66:135-9.
  29. Pont J, Albrecht W. Fertility after chemotherapy for testicular germ cell cancer. Fertil Steril. 1997; 68:1-5.
  30. Belker AM, Thomas AJ Jr, Fuchs EF, et al. Results of 1,469 microsurgical vasectomy reversals by the Vasovasotomy Study Group. J Urology. 1991; 145(3):505-11.
  31. Campbell JM, Harrison KL. Smoking and infertility. Med J Aust. 1979; 342-43.
  32. Osser S, Beckman-Ramierz A, Liedholm P. Semen quality of smoking and non-smoking men in infertile couples in a Swedish population. Acta Obstet et Gynecol Scandinavica. 1992; 71(3):215-8.
  33. Healy D, Schenken R, Lynch A, et al. Pulsatile progesterone secretion: its relevance to clinical evaluation of corpus luteum formation. Fertil Steril. 1980;41:114.
  34. Sherins RJ, Brightwell D, Sternthal PM. Longitudinal analysis of semen of fertile men. In: Troen P, Nankin HR, eds. The testes in normal and infertile men. New York: Raven Press, 1977.
  35. Rashef E, Daniel WW, Foster JC, Bradley EL, Blackwell RE, Younger JB. Accuracy of 1-hour versus 24-hour follow-up films in hysterosalpingography. Fertil Steril. 1989;52:753-55.
  36. Mackey RA, Glass RH, Olson LE, et al. Pregnancy following hysterosalpingography with oil and water soluble dye. Fertil Steril. 1971; 22:504-7.
Jacksonville Medicine / May, 2000

What's New · Northeast Florida Medicine Journal · Know Your Physician · Legal & Legislative
· DCMS Alliance · Academy of Medicine · Member Websites · Community Health
About the DCMS · Meetings Calendar · Member Benefits · Employment Connection · Home

Duval County Medical Society   ·   555 Bishopgate Lane  ·   Jacksonville, FL  32204
Phone: (904) 355-6561   ·     FAX:  (904) 353-5848   
General Email: dcms@dcmsonline.org    ·   Webmaster's Email: mdoran@dcmsonline.org
Privacy Policy and Disclaimers