Author's Note: The expert advisors for this article are James M. Goldfarb M.D., M.B.A., Director of Fertility Services, and Professor of Obstetrics & Gynecology at the Lerner College of Medicine, Cleveland Clinic Foundation, and Sandra P. Stewart, R.N., M.S., Clinical Nurse Specialist and Nurse Manager, both at the Cleveland Clinic Fertility Center in Beachwood, Ohio. Sandra Stewart is also my sister-in-law.

July 25, 2003 was the twenty-fifth birthday of Louise Brown, the first baby born after in vitro or assisted reproductive technology. Today, specialists in the field of Assisted Reproductive Technology (ART) marvel at the great good luck the doctors had in getting a successful outcome, given the technology, medications and plain old know-how that was not available in the 1970s.

Currently, in Western countries, about 10-15% of couples experience some difficulty with fertility. Remedies range from a visit to a primary physician, education and adjustments in timing attempts to conceive, to placing the entire reproductive process in the hands of a specialist. The Federal Centers for Disease Control (CDC) collects data (on treatment cycles) from fertility clinics on the special population of patients using assisted reproductive technology. Their latest figures, for women under 35, categorized causes as 40% female, 23% male, 17% combined male and female factors, 10% more than one female factor and 10% unexplained by any definable cause.

Currently, in Western countries, about 10-15% of couples experience some difficulty with fertility.

What is Infertility, Subfertility, Sterility?
Different words are used to define different situations. Definitions have changed, as technology has changed.

Sterility is the absolute inability to procreate: an absent uterus in women, absent testes in men. In years past, a woman with blocked fallopian tubes or man with an obstructed vas deferens would be sterile. But with assisted reproductive technology (ART), this is no longer the case.

Infertility is usually defined as no pregnancy after one year of unprotected intercourse. This is a relative measurement. Over time, many couples may achieve pregnancy. In five years, nearly one half of "infertile" couples will conceive.

Subfertility is used to describe gradations between normal fertility and sterility, often used interchangeably with infertility.

Fecundability is the pregnancy rate from one menstrual cycle. The normal rate in humans is 20%. Seventy-five percent of normally fertile couples are expected to have conceived in six months and almost 100% by one year.

Normal fertility can be considered from several different points of view: the couple, the female and the male. In this article, we are going to look at female fertility: the biological steps and mechanisms, the defects, the causes of the defects and what to do.

Three Basic Questions
There are really three basic questions that have to be answered when doctors try to determine why a woman is having problems getting pregnant.
  1. Is she ovulating?
  2. Is there a clear passage from the ovary to the uterus?
  3. How old is she?

A similar set of questions has to be answered in men. Is there sperm? Can it be delivered to the female? Is the sperm normal? In the male these questions are answered in a preliminary and rather thorough way by semen analysis. With women the process is more complicated. Before we look at causes and treatments, let's start with basic female function.

Normal Female Fertility

The female germ cells, called oogonia, lodge in the outer layer, or cortex, of the ovary. They divide rapidly and at the fifth month of a female fetus's life number up to 6-7 million cells. At that time, they begin maturation and are now called primary oocytes, eventually maturing to become primordial follicles. At birth, a female baby will have 2-4 million primordial follicles. In terms of numbers, birth is the high point, as many of the follicles will degenerate so that, by puberty, a woman will have, on average, about 400,000 of these follicles in her ovaries. It has been generally accepted that these are all the germ cells a woman has for her lifetime because these cells have not been known to multiply during life the way the spermatogonia do. Although there is one recent article that suggests that germ cells in the ovary may be able to regenerate later in life, in humans, for all practical purposes "what you have at birth is what you get for life" is still the case.

Follicle Development and Ovulation
Throughout female life from the onset of menstruation (menarche) to menopause, a small number of these primordial follicles are constantly beginning development. At puberty, hormones from the hypothalamus and pituitary glands in the brain will start to influence ovarian function. Without these hormones, the follices will not survive. The names of the hormones: gonadotropin releasing hormone (GnRH), follicle stimulating hormone (FSH) and luteinizing hormone (LH).

With respect to the ovary, the menstrual cycle is divided into two phases: the follicular phase and the luteal phase. The follicular phase is dominated by the development of the follicle under the influence of FSH, while the luteal phase is dominated by another pituitary hormone, luteinizing hormone (LH). LH and FSH cause the production of prostaglandins and enzymes that disrupt the follicle and release the ovum, or egg, from the ovary. This release into the peritoneal space at the open fringed end of the fallopian duct is called ovulation.

LH and FSH cause the production of prostaglandins and enzymes that disrupt the follicle and release the ovum, or egg, from the ovary.

As ovulation occurs, the egg divides. As the sperm enters the egg, the egg divides again, halving its 46 chromosomes so that it is now ready to combine with a 23-chromosome sperm to form the complete human cell (zygote).

Causes and Mechanisms of Female Infertility
The main causes of female factor infertility are ovulation disorders, tubal disease and endometriosis. In a population of infertile couples, if you consider unexplained and male factor infertility at about 25% each, ovulatory disorders and tubal factors would be about 20% each and endometriosis 5-10%, with small percentages for uterine/cervical problems.

The history and physical exam offer us many hints about the cause of infertility (Table 1):

Table 1.
Female Infertility Work-up: History and Physical Examination.
  • Systemic illnesses: weight gain, weight loss
  • Cancer, chemotherapy, radiation treatment, surgery
  • Urogenital system: surgery: D & C, laparoscopy
  • Pregnancy: outcome
  • Menstruation: regular, irregular, absent
  • Pelvic pain, dysmenorrhea, dyspareunia
  • Sexual history: function, sexually transmitted disease, pelvic inflammatory disease
  • Endocrine history: diabetes, thyroid disease

Family history
  • Infertility, cystic fibrosis, endometriosis

Medications & Drugs
  • Prescription: endocrine, psychoactive, anti-hypertensive

Physical exam
  • Height & weight, neck, arms (carrying angle)
  • Skin: hirsuitism
  • Breasts: galactorrhea
  • Abdomen: girth, adiposity
  • Mass Pelvic exam: uterus, ovaries, pelvic mass, tenderness Genital ulcers, warts

First Question: Is She Ovulating?
Defects in ovulation comprise about 25% of female fertility problems. The biggest clue that ovulation is occurring is the presence of regular menstrual periods. Regular periods are almost always associated with ovulation. Irregular or scanty menstruation (oligomenorrhea) or absent periods (amenorrhea) have to be investigated by your doctor.

It is impossible to describe all the conditions that affect ovulation, but let me hit the highlights and give you some examples of the mechanisms involved. Causes for ovulatory defects can be genetic, as in Turner's syndrome, or hormonal, as in prolactinoma or the polycystic ovary syndrome (PCOS). Deficient or excessive body fat can also lead to hormonal changes that stop ovulation.

Turner's Syndrome
Although most of these women are identified in infancy or childhood, a few may present for evaluation of infertility or for recurrent pregnancy loss. The classical features of Turner's — short stature, increased carrying angle of the arms, webbing of the neck — may be present and are clues to the diagnosis. For our purposes, the extremely poor development of the ovaries is the key feature. The number of primordial follicles is decreased and there is increased death of these follicles.

The majority of Turner's syndrome cases are diagnosed before childbearing is contemplated — at birth, during mid-childhood because of short stature or at expected puberty when they fail to develop. These latter patients may be supported with estrogen replacement to establish secondary sex characteristics (e.g., breasts) and optimal uterine development. Overall, 90% of patients will require hormone replacement.

The ability to produce eggs and support a pregnancy depend very much on the amount and quality of the ovarian tissue present. Some patients develop normally but when spontaneous pregnancy does occur, there is a high risk of chromosomal abnormalities in the fetus and recurrent pregnancy loss. Most patients will experience early ovarian failure. Patients with a normal uterus, either through normal development or estrogen support, may be able to achieve a pregnancy with donor eggs.

Because Turner's syndrome patients may have been born with a narrowed aorta, the main artery leading from the heart, any woman diagnosed with Turner's syndrome and considering pregnancy needs a preliminary full examination from a heart specialist because the narrowed aorta can make pregnancy very hazardous, even fatal.

Polycystic Ovary Syndrome (PCOS)
This syndrome gets its name from ovaries that are enlarged by many cysts beneath the ovarian capsule. The 1990 NIH Consensus Conference defined PCOS as oligomenorrhea (absent or very minimal menstruation) and hyperandrogenism (increased androgen, male hormone, production).

Elevated insulin levels, especially in obese patients, can increase ovarian and adrenal androgens and decrease sex hormone binding globulin (SHBG) secretion by the liver. The net effect is increased active androgen in the ovary and the circulation, inhibiting oocyte development. Increased insulin sensitivity (which leads to lower insulin levels) by weight loss or medication can permit ovulation in some of these women. Although not an approved FDA indication, metformin, an oral medicine used to treat diabetes by increasing insulin sensitivity, has been used alone or prior to ovarian stimulation to treat infertility. These patients do have adequate germ cells.

Hyperprolactinemia and Prolactinoma
Prolactin is a pituitary hormone made by specialized cells in the pituitary gland. Its main function is to stimulate breast development and milk production during and after pregnancy. The neurotransmitter dopamine regulates prolactin production. When dopamine interacts with these special cells, prolactin secretion is inhibited. Any influence that decreases the effect of dopamine or increases the number of specialized cells can result in excess prolactin secretion.

Benign tumors, called prolactinomas, cause what is considered primary hyperprolactinemia. Secondary causes would be drug inhibition of dopamine receptors, compression of the pituitary gland by another tumor or conditions that cause elevated growth hormone or thyroid stimulating hormone.

Any influence that decreases the effect of dopamine or increases the number of specialized cells can result in excess prolactin secretion.

Excess prolactin has several effects that can interfere with ovulation: decreased secretion of GnRH, inhibition of LH and FSH release, and inhibition of both estrogen and progesterone secretion in the ovary. Besides amenorrhea and infertility, women with elevated prolactin may experience galactorrhea (spontaneous flow of milk from the nipple).

Normal blood prolactin levels are around 25 micrograms in women. A level up to 100 micrograms is often from secondary causes — medication, physical compression or another endocrine condition. Higher levels are most often associated with prolactinomas.

Elevated prolactin is treated with the dopamine agonists, bromocriptine and cabergoline. Bromocriptine is preferred in fertility treatment because of its safety record in pregnancy.

Body Weight and Fertility
Both excess and low body weight are associated with infertility in women. In obesity, the mechanism is probably similar to that of PCOS. Insulin resistance and high insulin levels stimulate androgen production and decrease sex hormone binding globulin (SHBG), resulting in more circulating male hormone (androgen) which, in turn, inhibits follicular development. Weight loss restores fertility. Increasing insulin sensitivity with metformin can also be effective.

Women who are extremely thin can also experience amenorrhea. They have low gonadotropin and estrogen levels, as well as absent periods. Because deficient GnRH secretion is thought to be responsible, this type of amenorrhea is called hypothalamic, or functional. These women have low body fat stores and/or energy deficits without any other demonstrable cause for a GnRH deficit. The most common conditions are starvation, abundant exercise or eating disorders.

Currently, investigators think that the mediator for this effect is the fat cell hormone leptin. The amount of circulating leptin is proportional to the fat cell mass. A critical amount of leptin is required for menarche in girls. Slender women with this type of amenorrhea have lower leptin levels than matched controls. A recent study showed that synthetic leptin increased LH and estradiol, and promoted follicular development and even ovulation in some patients without menstrual periods because of strenuous exercise or low body weight.

Second Question: Is There a Clear Passage From the Ovary to the Uterus?
The two main conditions that can affect the fallopian tubes are endometriosis and tubal infection.

In this condition, implants of endometrial tissue are found outside the uterine cavity, primarily in the pelvis, on the ovaries, tubes, body linings and adjacent organs of the GI and GU tracts. This extra endometrial tissue responds to cyclical estrogen and progesterone in the same way the uterine endometrium does — proliferating, swelling and bleeding. The implants can invade the surrounding tissues, affect nerve endings, and cause scarring and adhesions on adjacent peritoneal surfaces. The most common symptoms of endometriosis are pelvic pain, painful periods (dysmenorrhea) and painful sexual intercourse (dyspareunia). These symptoms generally coincide with menstruation but can become chronic. That said, there are women who have had no complaints at all and are found to have endometriosis at laparoscopy or surgery.

The most common symptoms of endometriosis are pelvic pain, painful periods (dysmenorrhea) and painful sexual intercourse (dyspareunia).

The severity of endometriosis is divided into stages that depend on the size and depth of the endometrial implants and the thickness of the adhesions. Sizable masses, called endometriomas or chocolate cysts, can develop as cystic structures. The stages are:
  1. minimal, with a few superficial implants;
  2. mild, more numerous implants, filmy adhesions;
  3. moderate, more numerous and larger implants, dense adhesions; and
  4. severe, more dense adhesions, larger implants, endometriomas.
In Stages III and IV the adhesions can cause distortion of the oviduct.

There is no dispute that Stage III and IV endometriosis, with distortion of tubal anatomy and involvement of ovarian surfaces, can cause infertility. Studies have shown that surgical treatment can improve fertility. But whether endometriosis in its minimal or mild forms has any effect on fertility is in dispute. Many studies have shown that treatment resulted in no improvement in fertility, while others have demonstrated a benefit. This controversy notwithstanding, treatment of endometriosis to prevent progression to more severe stages and to address pain symptoms is certainly indicated at any stage.

Surgical treatment by laparoscopy or laparotomy aims to destroy implants by electrocautery or laser, to dissolve adhesions, and evacuate or remove cysts. The goal is to restore normal anatomy to allow fertilization to occur. Medical treatment (i.e., hormonal therapy) has not been shown to restore fertility. The aim of hormonal therapy is to relieve pain and decrease or eliminate extra-uterine implants. The therapy suppresses cyclical hormone secretion and, of course, ovulation, and often induces an artificial menopause. Androgens, GnRH, birth control pills, progesterone alone, selective estrogen or progesterone receptor inhibitors have all been used in the treatment of endometriosis.

Pelvic Inflammatory Disease (PID) / Salpingitis
PID is the most common cause of tubal factor infertility. The infection involves the upper genital tract (the uterus, the fallopian tubes and the ovaries) and structures around these organs. The infection of the fallopian tube (salpingitis) is the most crucial element causing infertility. The fallopian tube is lined with special, ciliated cells that direct the egg toward the sperm and the fertilized egg into the uterine cavity. Infection can destroy these cells and distort and/or block the tube.

The main bacterial culprits are Neisseria gonococcus (NG) and Chlamydia trachomatis (CT). NG is directly kills the special cells; CT probably destroys cells through immunological mechanisms. With the infection, the tubes can become thickened, distorted and blocked. Abscesses can form between the tube and the ovary or in the adjacent pelvis, and can be life threatening. This condition requires prompt, broad-spectrum antibiotic treatment. Interestingly, in about half of cases of tubal infertility secondary to PID, there is no history of acute infection. Chlamydia in particular can linger in the genital tract, causing ongoing subclinical damage. Chronic pelvic pain, infertility and ectopic pregnancy (where the pregnancy develops in the tube instead of the uterus) are the serious consequences of PID.

PID begins in the lower genital tract and moves upward. It results primarily from infections described above and contracted from the male partner. Risk factors are youth (75% of infections at age 25 or younger), menstruation, multiple partners, no contraception, a history of a sexually transmitted disease and surgical instrumentation. A previous episode of PID increases the likelihood of a subsequent infection. Teenagers are particularly susceptible because of immature cervical anatomy. Oral contraceptives are protective because they thicken the cervical mucus and shorten the menstrual periods. Barrier contraceptives interrupt transmission; spermatocides can also kill these germs.

For a long time, the intrauterine device (IUD) was thought to increase the likelihood of PID.3 Recent evidence shows that risk is increased only during the first 20 days after insertion. Earlier reports reflected the complications secondary to the Dalkon Shield, implicated in several deaths. The currently used copper and progesterone IUDs have not been associated with such complications.

We now know that Chlamydia is the most common pathogen, with four times the incidence of NG. In high-risk populations, the two infections are frequently seen together. Blood and urine tests for both NG and CT are now available. Cervical sampling can be done at the time of a pelvic exam and is routine in populations where risk is high.

Infection should be treated promptly and thoroughly, covering both NG and CT. Single dose regimens are useful when there is a question about compliance or follow up opportunities. It is crucial to treat the infected partner in order to prevent recurrent infection. Treatment regimens are subject to frequent updates because antibiotic-resistant strains emerge. The CDC is the best source for current guidelines.

It has been shown that the presence of hydrosalpinges reduces the success rates of IVF by as much as 50%.

The key diagnostic tests for PID-related medical problems are hysterosalpingogram (HSG) and laparoscopy. In HSG, water-soluble radioopaque dye is injected into the uterine cavity. Normally, it courses through the fallopian tubes and into the abdominal cavity. The procedure will detect distortions and obstruction of the uterine cavity and the fallopian tubes.

Laparoscopy examines the anatomical appearance and relationships of the tubes and ovaries, and locates adhesions and masses. A formerly infected tube may be dilated and contain sterile fluid — called a hydrosalpinx. The ovary may be covered with adhesions, or there may be dense adhesions between the tube and ovary associated with a scarred mass — called a tubo-ovarian complex.

In very mild cases, the performance of the salpingogram may, by itself, open the tube. Surgical treatment, usually by laparoscopy, seeks to open the end of the tube and release the scar tissue distorting the tube and the ovary. Performing these procedures in mild disease can result in pregnancy. In more severe disease, the rates of success plummet. The bottom line is that if there is great destruction of the tubal lining and anatomy, fertilization (which takes place in the portion of the tube nearest the ovary) is less likely. If fertilization does occur, the risk of abnormal implantation of the fertilized egg in the tube (ectopic pregnancy) increases substantially.

Operative intervention for severe disease is generally reserved not for treatment but for removal of fluid filled fallopian tubes (hydrosalpinges) prior to in vitro fertilization (IVF). It has been shown that the presence of hydrosalpinges reduces the success rates of IVF by as much as 50%.

The Role of Surgery in Endometriosis and PID

It is interesting to contrast the role of surgery in endometriosis and PID for the purpose of restoring fertility. In endometriosis, current opinion holds that treatment of mild disease is not likely to enhance fertility but treatment of moderate or severe disease will. In PID, treatment of mild disease is likely to improve fertility but treatment of moderate or severe disease is much less effective and incurs a high risk of ectopic pregnancy, so that in vitro fertilization is preferred.

Third Question: How Old Is She?
Fertility decreases with age. Nationally, in assisted reproductive technology facilities, live birth rates are 37% for women <35 and 4% for women >42.14,15 As mentioned earlier, there are only so many primordial follicles present in the ovary at birth and they decrease steadily until the time of menarche, from 2-4 million to 400,000. With every cycle, primordial follicles are lost. As women age, more chromosomal abnormalities occur during cell division of the ova. The decreasing numbers of follicles, cycles without ovulation (anovulatory) and poor quality of the ova all combine to diminish the chances of older women, especially after age forty, becoming pregnant.

While age is the strongest predictor of a women's ovarian function, there are some tests that are also helpful. They are the follicle count, which is determined by ultrasound, and blood tests for follicle stimulating hormone (FSH) and estradiol. All these tests are performed on or about the third day of the menstrual cycle. Follicle count is used because the number of small follicles seen on Day 3 gives a good idea about ovarian reserve.

The hormone levels give indirect evidence about ovarian reserve because inhibin, secreted by cells of the follicles, effects the hormone FSH. As the follicle number diminishes, there are fewer cells producing inhibin and FSH increases. As the specialized cells, called granulosa cells, continue to diminish, ovarian estrogen decreases despite elevated FSH. A high FSH and a low estrogen indicate severe loss of follicles.

Maximizing Female Fertility

Inducing Ovulation
Several drugs can be used to induce ovulation. The most common, and only FDA approved oral agent, is clomiphene citrate (Clomid® or Serophene®). Clomiphene is a weak estrogen that interferes with signals from the body's natural estrogen to decrease GnRH release. GnRH, in turn, stimulates FSH and LH. Another oral agent that has been used for the last several years, although not FDA approved for ovulation induction, is letrozole (Femara®), a drug used in the treatment of breast cancer. Letrozole directly lowers the production of estradiol from the ovary. Oral agents are generally the first line treatment for ovulatory dysfunction.

When oral agents do not work, injectable medications consisting of gonadotropins, either FSH alone or a combination of FSH and LH, can be used. Gonadotropin therapy is associated with a higher incidence of the most significant adverse effect of ovarian stimulation - multiple pregnancy. With the gonadotropins, the incidence of triplets is 8-10% and the incidence of quadruplets and higher is 1-2%, especially in younger women. These "high order multiple pregnancies" carry enormous risks, both to the mother and to the offspring. For example, among triplets as compared to singletons, the incidence of cerebral palsy is 30-fold higher.

Donor Eggs
Women who are not conceiving because of diminished ovarian reserve are quite capable of carrying a pregnancy to term and their live birth rates, using eggs harvested from donors, are similar to the rates for younger women. There are three sources of donor eggs:
  1. known donor — friend, relative
  2. shared donor — younger woman going through IVF for herself shares her eggs with a woman who cannot make eggs
  3. Anonymous paid donor — women who are recruited to donate eggs and are paid for their time and effort.

Cryopreserving and Reimplanting Ova or Ovarian Tissue
Chemotherapy and radiation therapy destroy ovarian germ cells and can produce infertility. One strategy is to freeze fertilized eggs or embryos at very low temperatures (cryopreserving) that are produced before cancer treatment. It is possible to cryopreserve ova, although they are, compared to sperm, much more susceptible to deterioration. This technique is considered experimental at present.

Women who are to receive pelvic irradiation can have a procedure called ovarian transposition. Their ovaries are surgically moved out of the field of radiation so the radiation does not destroy their ovarian function. Another procedure, still in the experimental stage, is cryopreservation of ovarian tissue. Recently, researchers described the first live birth resulting from ovarian tissue that was removed prior to chemotherapy, cryopreserved and then reimplanted in a woman's pelvis after her treatment for Hodgkin's disease.

Summary and Conclusions
Female fertility can be limited or diminished or destroyed in a number of ways. Women have a finite number of germ cells and follicles that are available for a limited period, from menarche to menopause, during their lifetimes. The process of ovulation is mediated by the interactions of hypothalamic, pituitary and ovarian hormones. Interference with ovulation can occur at any one or combinations of these sites. The oviducts can be distorted or blocked by the consequences of endometriosis or infection. The quality of the ova and spontaneous pregnancy decrease steadily with age. Drugs are available that stimulate ovulation and donor eggs can be used. The cryopreservation of ova or ovarian tissue are techniques now receiving research attention.