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Female Infertility

Diagnosis and Management

The diagnosis of female infertility is significantly more complex than the diagnosis of male infertility. A man’s infertility testing can be as simple as semen analysis, yet a woman may undergo extensive testing and screening, which may or may not result in a clear diagnosis. Women not only provide the egg, but they also provide a suitable environment for the embryo to develop into a viable human being. Although causes of female infertility are usually related to the woman’s eggs, several other ovarian and/or uterine conditions can interfere with the ability to conceive naturally. There are some established guidelines for diagnosing primary female infertility, however, all infertility workups should begin with an accurate medical history. The following questions can help guide the diagnosis and treatment of primary female infertility:
 
  • Have you ever had a miscarriage? If so, at what point during the pregnancy did the miscarriage occur?
  • Do you have a family history of infertility?
  • Do you have regular menstrual cycles?
  • Have you recently been screened for infectious diseases, including sexually transmitted diseases?
  • Do you own pets?
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Answers to each of these questions can provide important information to the fertility specialist. For example, owning pets can increase a woman’s likelihood of acquiring infections that can cause infertility, such as toxoplasmosis. Similarly, a family history of infertility could point to genetic causes of infertility. During any infertility workup, patients should settle for nothing less than a comprehensive medical history. A copy of our medical history form is on our “Contact” page. Of course, the questionnaire is just the beginning of an infertility workup. These questions can help identify potential causes of infertility, but the next step is to assess the reproductive physiology of both the male and female patient. In particular, hormone testing can provide information about a woman’s ovarian function and help guide treatment.

Most cases of female infertility are due to problems with ovulation. Anovulation (the absence of ovulation) suggests there is a problem at some stage of the ovarian cycle. A sign that a woman may not be ovulating would be irregular or absent menstrual periods. Most cases of anovulation are due to a hormonal problem of either the hypothalamus or the pituitary gland. The pituitary gland not only releases FSH and LH, but it also controls the release of many other hormones such as thyroid stimulating hormone and prolactin. Thus, a variety of disorders of the pituitary gland may interfere with a woman’s ability to conceive. In some cases, growing follicles may not reach ovulation due to hormonal problems. In other cases, a woman may ovulate, but the eggs are not capable of fertilization. Some of these conditions will be discussed in more detail later in this chapter.

Other common causes of female infertility include the following:

  • Damaged fallopian tubes – Blocked fallopian tubes due to pelvic inflammatory disease, endometriosis, or a previous ectopic pregnancy as well as the surgical removal of a fallopian tube can significantly affect a woman’s fertility. The fallopian tube is the site of fertilization. Thus, if the fallopian tubes are blocked, damaged, or missing, then fertilization cannot occur naturally.

  • Physical problems with the uterus – The uterus is where the embryo develops into a baby. Thus, conditions, such as fibroids or polyps, that interfere with an embryo implanting in the uterine wall or with the development of a fetus are not favorable for pregnancy.
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  • Cervical weakness – Any condition that impairs the ability of the cervix to remain closed can prevent a woman from carrying a fetus to term.
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  • Infectious diseases –  A variety of sexually and non-sexually transmitted infectious diseases can result in implantation failure or the loss of a pregnancy. Thankfully, most of these diseases are relatively easy to test for during a standard infertility workup.
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  • Immunological problems – An abnormal immune system can result in a woman’s body attacking an implanting embryo, causing implantation failure or early pregnancy loss. Anti-sperm antibodies may also be present in vaginal secretions or blood, which can prevent fertilization.
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  • Blood clotting disorders – Thrombophilia (a condition that increases the chance of blood clotting) can increase a woman’s risk of miscarriage. Thrombophilic disorders can also interfere with embryo implantation, because a blood clot can form at the site of implantation. Many inherited thrombophilias can be identified by routine blood tests.
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  • Stress – Physical and emotional stress can cause female infertility. Stress can have several physiological manifestations, making it more difficult to conceive.
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  • Lifestyle –  A woman’s lifestyle habits can directly impact her ability to conceive. Several studies have established links between cigarette smoking and infertility. Similarly, alcohol consumption has been found to have a dose-dependent association with infertility.
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There are also number of gynecological conditions that frequently lead to female infertility, including polycystic ovarian syndrome, endometriosis, and uterine fibroids.

Aging decreases a woman’s chances of having a baby in the following ways:
– The ability of a woman’s ovaries to release eggs ready for fertilization declines with age.
– The health of a woman’s eggs declines with age. With advanced ages, more genetic problems are observed due to aging of the eggs.
– As a woman ages she is more likely to have health problems that can interfere with fertility.
– As a women ages, her risk of having a miscarriage increases.

How long should women try to get pregnant before calling their doctors?
Most healthy women under the age of 30 shouldn’t worry about infertility unless they’ve been trying to get pregnant for at least a year. At this point, women should talk to their doctors about a fertility evaluation. In some cases, women should talk to their doctors sooner. Women in their 30s who’ve been trying to get pregnant for six months should speak to their doctors as soon as possible. A woman’s chances of having a baby decrease rapidly every year after the age of 30. So getting a complete and timely fertility evaluation is especially important.

Where to begin?
The first step in infertility testing and assessment starts at your gynecologist’s office. A base line ultrasound scan (sonogram) will be useful for antral follicle tracking (to see how many potential eggs each ovary contains). This should be done on day 2 or day 3 of your menstrual period. Similarly, on this very same day, you should ask for hormone testing in order to make an assessment of your ovarian function including FSH, LH, Estradiol, Prolactin, TSH and AMH. Based on these test results, we will be able to make an assessment and decide on the most appropriate course of action. For more information about preliminary testing and how to get started, please visit “Infertility Testing” section.

How Does Age Affect Female Fertility?

Age is one of the most critical factors when considering a woman’s likelihood of success during an IVF treatment. It is not the “age” as a number per se that affects a woman’s ability to conceive, but rather, it is the impact on ovarian reserves and oocyte quality that impairs a woman’s ability to conceive. Each woman is born with a limited set of ovarian reserves and the number of eggs in the reserves decline with age. There is no new oocyte production in the ovaries, therefore, fertility declines every month with every menstrual cycle. The following figure shows the amount of ovarian reserves by age:

Every woman is born with approximately 1 million follicles in the ovarian reserves (a follicle is a cyst which contains the egg). Once menstruation begins in puberty, the ovarian reserves start to decline with every menstrual cycle.

Around the age of 30, the ovarian reserves fall down to 10% of what they were at birth. In other words, between puberty and the age of 30, a woman loses 90% of her ovarian reserves and the decline becomes even sharper afterwards. Between the ages of 40 and 50, the ovarian reserves will have highly diminished and the quality of reserves will make pregnancy very difficult to achieve.

How does age affect infertility?

Female Infertility from a Scholarly Perspective


Understanding Infertility: The Biology of Human Ovulatory Process
By Asst. Prof. Dr. Ahmet Ozyigit

I. Introduction
Infertility is broadly defined as inability to conceive for at least one year while having regular sexual intercourse without use of any means of contraception (1).  Conceiving in itself is not a sufficient definition of fertility; therefore, women who are able to conceive but cannot carry pregnancy to a full term can also be included in the definition of infertility (2). Given that a woman’s age is probably the most important factor affecting her ability to conceive, women over the age of 35 can be considered for fertility assessment after six months of having regular sexual intercourse without pregnancy (3). Besides age, there are a number of factors that can potentially interfere with a woman’s fertility. By anatomic location, causes of female infertility can be broadly categorized as ovulatory factors, tubal/peritoneal factors, uterine factors, cervical factors and vaginal factors. Each factor can potentially interfere with a female’s ability to conceive and/or to maintain pregnancy to a full term. If we look at pregnancy as a process which involves a chain reaction of all of these factors, among these, ovulatory factors can be perceived as the brains of the whole operation given that no ovulation (anovulation) will simply make the rest of the pregnancy process obsolete. Studying the events in female reproduction that lead to ovulation of the egg thus allowing fertilization to occur will help us make a better assessment of ovulation problems and create appropriate treatment solutions.

II. Historical Background
Our understanding of anovulation and its impact on infertility can be traced back to the original work of Crowe et. al. where they discover the role of pituitary gland on female and male reproduction. In 1910, the authors study the effects of partial ablation of the pituitary gland in adult dogs and puppies, where they find that in adult dogs, the result is atrophy of the genital organs while in puppies, they observe perpetuation of infantilism and sexual insufficiency (4). A few years later, a new discovery comes from Aschner with respect to the hypothalamus-pituitary interaction. Aschner’s proposition was rested on his own observations that existence of lesions between the hypothalamus and the pituitary gland due to a head injury resulted in hypopituitarism and gonadal atrophy (5,6).  These early studies on the pituitary gland laid the foundation for further research and clinical studies. In 1926, Zondek’s study took field research one step further and revealed that immature animals exhibited rapid development of sexual puberty when they received an implant of the anterior pituitary from adult animals (7). In the very same year, Smith also showed that daily implantation of pituitary gland tissue from mice, cats, rats, rabbits and guinea pig into immature female rats and mice caused enlargement of the ovaries and superovulation (8). Finally, in 1967, the link between the hypothalamus and the pituitary was pronounced with solid grounds by Guillemin. His study revealed that GnRH, which is synthesized and released at hypothalamus, controls the release of gonadotrophins (FSH and LH) from the pituitary for follicle growth (9). Today, we have a better understanding of the role of the pituitary gland on ovulation, and therefore, its potential effects on female infertility.

III. The role of Pituitary Gland in Female Fertility
The pituitary gland operates as the middleman between hypothalamus and the target organs. It consists of two separate sections; the adenohypophysis, including the anterior and intermediate lobes, and neurohypophysis, which consists of the posterior lobe. The adenohypophysis is made up of six endocrine cells. These are, somatotrophs, lactotropes, thyrotrophs, corticotrophs, gonadotropes and melanotropes (10, 11). Somatotrophs secrete growth hormone and regulate growth and metabolism; lactotropes produce the prolactine hormone, which regulates milk production in females; thyrotrophs produce the thyroid stimulating hormone (TSH) which stimulates the thyroid hormone as well as thyroid follicle development, corticotropes regulate metabolic function, melanoropes regulate melanin production and finally, Gonadotropes are responsible for the production of follicle stimulating hormone (FSH) and the luteneizing hormone (LH) in response to GnRH, which both maintain reproductive function (10,11). TSH, LH, and FSH are glycoproteins composed of a common α-subunit (αGSU) coupled with a hormone-specific β-subunit (11,12). Jameson et al., in their 1989 study, have shown that in some neoplasms, there tends to be less rigorous control of the α-gene expression compared to the β-gene expression (13). This is also evidenced by a later study, which shows that estradiol at the pituitary gland level does not directly regulate steady state levels of mRNA for α-subunits while there exists a direct negative relationship with the β-subunits (14).

IV. Research and Clinical Work
FSH, which is a direct production of the pituitary gland, plays a role in the ovary in follicular maturation as well as production of estrogen in the granulose cells (15). LH, on the other hand, controls the length and sequence of a menstrual cycle. The luetinizing hormone also controls ovarian production of estrogen and progesterone and prepares the uterus for a successful implantation of the embryo (16). As a respponse to GnRH, both hormones are secreted in a pulsatile fashion, but the pulses of FSH are more subtle compared to the LH, because of the prolonged circulatory half-life of FSH which is attributed to differences in the composition of its carbohydrate side chains (15). Serum levels of FSH and LH measurements help clinicians have an understanding of female ferility and ovarian function. An elevated level of FSH, for instance, corresponds to reduced gonadal function while a normal serum level indicates normal function. An elevated LH level coupled with a normal FSH level can be an indication of polycystic ovary syndrome (17). Knowledge of these measurements have allowed clinicians to take appropriate action when offering fertility treatments. With the aid of research on the function of the pituitary and the hypothalamus-pituitary interaction, a number of treatment alternatives are available for infertile couples with ovulationary problems. The following are borad categories of these treatment options:

1- Clomifene citrate: Clomifene citrate is often the first choice of ovulation induction in women with ovulatory problems and normal estrogen levels. Even though there is no consensus whether clomifene has an estogenic or an anti-estrogenic effect at the pituitary and ovarian level, it has been reported that it causes a more than fifty percent increase in the endogenous FSH level (18). With increased levels of FSH, clomifene treatment aims to recruit a dominant follicle and therefore generate ovulation in order to increase the chances of pregnancy. Climofene citrate can be used in a woman’s natural cycle with timing of sexual intercourse and can also be used in an Intra Uterine Insemination (IUI) cylce. An IUI cycle can be based on a sole use of clomifene citrate or can be used in conjunction with gonadotropin supplements.

2- Gonadotrophins: Women who do not respond to climofene, or who has depleted ovarian reserves have a higher chance of conception through direct injection of gonadotrophins. Introducing FSH in earlier days of the menstrual cycle, i.e. follicular phase, will prolong the follicle recruitment phase and therefore allow more follicles to be recruited for development. A higher number of follicles recruited for ovulation will increase the chances of conception, but will also increase the risk of a multiple pregnancy. With the use of gonadotrophins, a GnRH agonist or a GnRH antagonist protocol may be implemented. An agonist protocol, which tends to be more popular, helps suppress both FSH and LH concentrations prior to ovulation induction, and avoid prematuire luteinization (19). An antagonist protocol may be preferred for poor responder women with lower ovarian reserves (20).  Antagonist protocols have been associated with lower gonadotrophin requirements, and shorter stimulation cycles in poor responders (21).

Use of gonadotrophins can be in the form of pure FSH or a combination of FSH and LH. While FSH supplementation alone is sufficient for follicle recruitment and growth, small amounts of LH can be useful in provision of adequate estrogen secretion and can also have a direct impact on stimulation and modulation of folliculogenesis (22,23).

V. Conclusion
Continuous research in the field of infertility helps researchers provide a better account of infertility problems and also helps clinicians provide better formulated treatment protocols for their patients. The comprehensive history of research on the role of pituitary gland on reproductive organs has helped formulate treatment options for infertile couples such as climofene citrate and gonadotrophin supplementations. Both treatments have been derived from the principle of hormone synthesis and secretion from the pituitary gland as a response to GnRH released from the hypothalamus.

References
1. Zabrek EM. Can I get pregnant? The basic infertility workup. Clin Obstet Gynecol 1996; 39: 223-230.
2. Gaware. V. M. et al. Female infertility and its treatment by alternative medicine: A review. Journal of Chemical and Pharmaceutical Research, 2009, 1(1):148-162
3. Roupa. Z. Et al. Causes of infertility in women at reproductive age. Health Science Journal, 2009 3(2): 80-87
4. Crowe SJ, Cushing H and Homans J. Experimental hypophysectomy. Bulletin of Johns Hopkins Hospital, 1910; 21: 127–167
5. Lunenfeld, Historical Perspectives in Gonadotrophin Therapy. Human Reproduction Update, 2004, 10(6): 453–467.
6. Aschner, B. Ueber die Beziehung zwischen Hypophysis und Genitale. Arch Gyna 1912, (97): 200–227.
7. Ludwig M. et al. Ovarian Stimulation: From basic science to clinical application. Reproductive Biomedicine Online, 2002; 5(1): 73-86
8. Smith, P. E. Hastening of development of female genital system by daily hemoplastic pituitary transplants. Proc Soc Exp Biol Med, 1926; 24: 1311–1333.
8. Zondek, B. Ueber die Hormone des Hypophysenvorderlappens. Klin Wochenschrift, 1930; 9: 245–248.
9. Guillemin, R. Chemistry and Physiology of hypothalamic releasing factors for gonadotrophins. International Journal of Fertility, 1967; 12: 359-367
10. Nolan, T.E. Regulation of GnRH Receptor mRNA: Interaction of GnRH and Estradiol. Colorado State University, Fort Collins. 1997; ADA333377.
11. Zhu X. Molecular physiology of pituitary development: signaling and transcriptional networks. Physiol Rev, 2007; 87:933
12. Pierce, J. G, Parsons, T. F, Glycoprotein hormones: structure and function. Annu Rev Biochem, 1981; 50:465–495
13. Jameson J.L, Powers A.C, Gallagher G.D and Habener J.F, Enhancer and Promoter Element Interactions Dictate Cyclic Adenosine Monophosphate Mediated and Cell-Specific Expression of the Glycoprotein Hormone oc-Gene. Molecular Endocrinology, 1989; 3: 763-772
14. DiGregorio G.B, Nett T.M, Estradiol and progesterone influence the synthesis of gonadotropins in the absence of gonadotropin-releasing hormone in the ewe. Biology of Reproduction, 1995; 53(1): 166-172
15. Huhtaniemi I.T, Aittomaki K. Mutations of follicle-stimulating hormone and its receptor: effects on gonadal function, Eur J Endocrinol. 1998; 138(5):473-81.
16. Kumar P, Sait S.F. Luteinizing hormone and its dilemma in ovulation induction. J Hum Reprod Sci, 2011; 4(1): 2-7
17. Balen A.H, Conway G.S, Kaltsas G, Techatrasak K, Manning P.J, West C, Jacobs H.S, Polycystic ovary syndrome. The spectrum of the disorder in 1741 patients. Hum Reprod, 1995; 10:2107–2111
18. Kousta, E, White D.M., and Franks, S. Modern use of clomiphene citrate in induction of ovulation. Human Reproduction Update, 1997; 3(4): 359–365
19. Homburg, R. and Insler, V. Ovulation induction in perspective, Human Reproduction Update, 2002; 8(5): 449-462
20. Pu, D., Wu, J, and Liu, J. Comparison of GnRH antagonist versus GnRH agonist protocol in poor ovarian responders undergoing IVF, Hum Reprod, 2012; 27(4):1230
21. Lainas T.G, Sfontouris I.A, Zorzovilis I.Z, Petsas G.K, Lainas G.T, Alexopoulou E, et al. Flexible GnRH antagonist protocol versus GnRH agonist long protocol in patients with polycystic ovary syndrome treated for IVF: a prospective randomised controlled trial (RCT) Hum Reprod. 2010; 25: 683–689.
22. Couzinet B, Lestrat N, Brailly S et al. Stimulation of ovarian follicular maturation with pure follicle-stimulation hormone in women with gonadotropin deficiency. Journal of Clinical Endocrinology and Metabolism, 1988; 66: 522–526.
23. Filicori M, Cognigni G.E, Taraborrelli S et al. Luteinizing hormone activity in menotropins optimizes folliculogenesis and treatment in controlled ovarian stimulation. Journal of Clinical Endocrinology and Metabolism, 2001; 87: 1156–1161.