Infertility Management

Ovulation induction medications, often referred to as fertility drugs, are used to stimulate the follicles in your ovaries resulting in the production of multiple eggs in one cycle. The medications also control the time that you release the eggs, or ovulate, so sexual intercourse, intrauterine inseminations, and in vitro fertilization procedures can be scheduled at the most likely time to achieve pregnancy.

There are risks associated with the use of ovulation induction medications including an increase in the chance for high order multiple births and the development of ovarian cysts. A rare side effect that can occur is ovarian hyperstimulation syndrome (OHSS); symptoms include severe pain in the pelvis, abdomen and chest, nausea, vomiting, bloating, weight gain and difficulty breathing.

The medications most commonly used in fertility treatment are clomiphene citrate, gonadotropins, Metformin and Parlodel.

Clomiphene Citrate (Clomid, Serophone)
This medication comes in a tablet form and is used for women who have infrequent periods or long menstrual cycles. Common side effects include headaches, blurred vision and hot flashes.
 

Gonadotropins (Repronex, Follistim, Bravelle, Pergonal and GonalF)
This is an injectable medication that is used to induce the release of the egg once the follicles are developed and the eggs are mature. Side effects may include abdominal distention/discomfort, bloating sensation, mood swings, fatigue or restlessness. In most cases, the side effects are relieved by follicular aspiration.
 

Glucophage (Metformin)
Metformin is given to patients as an insulin lowering medication. Most commonly used in PCOS patients, the medication has been shown to reverse the endocrine abnormalities seen with polycystic ovary syndrome within two or three months. The use of Metformin can result in decreased hair loss, diminished facial and body hair growth, normalization of elevated blood pressure, regulation of menses, weight loss and normal fertility.
 

Parlodel
Parlodel is a medication used to lower prolactin levels. It will also reduce pituitary tumor size, should one be present. An oral medication taken with meals, Parlodel has few side effects and is relatively inexpensive.

There are different levels of ovulation induction commonly used to treat infertility related to ovulation disorders, male factor or unknown causes. One method of treatment involves clomiphene citrate (Clomid or Serophene) taken in pill form for 5 days at the beginning of a cycle. For women whose only infertility problem is anovulation, up to 80% of patients will ovulate using this medication and 50% of those will conceive . Clomiphene may be combined with intrauterine insemination to boost the success of the medication by placing the sperm and egg in closer proximity to each other.

The more aggressive level of ovulation induction is called superovulation. This treatment uses gonadotropins or sometimes a combination of clomiphene and gonadotropins to stimulate the production of multiple eggs. Patients undergoing superovulation must be closely monitored by blood tests and ultrasounds. Monitoring ensures that the patient does not hyperstimulate and also helps the physician administer the correct dosage of medication so that only a few follicles develop. This is a critical step to keeping the multiple pregnancy rates low. At the end of the superovulation treatment process, a low dose HCG (human chorionic gonadotropin) may be prescribed to stimulate ovulation. Ovulation will occur between 24-36 hours after HCG. The patient is instructed to either have intercourse during this time or to come in for an intrauterine insemination. Depending on the cause of infertility, the success rate per superovulation treatment cycle is approximately 10-20% based on the woman's age.

New ovulation induction fertility treatment options for women with PCOS
Manual of Ovulation Induction

The follicular phase (or proliferative phase) is the phase of the estrous cycle, (or, in humans and great apes, the menstrual cycle) during which follicles in the ovary mature. It ends with ovulation. The main hormone controlling this stage is estradiol

Hormonal events
Follicle recruitment
Estrogen surge LH surge and ovulation

Follicular waves

References

Hormonal events

Follicle recruitment

Follicle-stimulating hormone (FSH) is secreted by the anterior pituitary gland. FSH secretion begins to rise in the last few days of the previous menstrual cycle,[2] and is highest and most important during the first week of the follicular phase.[3] The rise in FSH levels recruits five to seven tertiary-stage ovarian follicles (this stage follicle is also known as a Graafian follicle or antral follicle) for entry into the menstrual cycle. These follicles, that have been growing for the better part of a year in a process known as folliculogenesis, compete with each other for
dominance.[citation needed]

FSH induces the proliferation of granulosa cells in the developing follicles, and the expression of luteinizing hormone (LH) receptors on these granulosa cells. Under the influence of FSH, aromatase and p450 enzymes are activated, causing the granulosa cells to begin to secrete estrogen. This increased level of estrogen stimulates production of gonadotropin-releasing hormone (GnRH), which increases production of LH.[2][3] LH induces androgen synthesis by thecal cells, stimulates proliferation, differentiation, and secretion of follicular thecal cells and increases LH receptor expression on granulosa cells.[3]

Throughout the entire follicular phase, rising estrogen levels in the blood stimulates growth of the endometrium and myometrium of the uterus.[4] It also causes endometrial cells to produce receptors for progesterone,[4] which helps prime the endometrium to respond to rising levels of progesterone during the late proliferative phase and throughout the luteal phase.

Estrogen surge

Two or three days before LH levels begin to increase, usually by day seven of the cycle, one (or occasionally two) of the recruited follicles has emerged as dominant. Many endocrinologists believe that the estrogen secretion of the dominant follicle has increased to a level that GnRH production is suppressed, which lowers the levels of LH and FSH. This slowdown in LH and FSH production leads to the atresia (death) of most of the recruited follicles, though the dominant follicle continues to mature. Estrogen levels will continue to increase for several days (on average, six days, but this varies widely).

These high estrogen levels initiate the formation of a new layer of endometrium in the uterus, histologically identified as the proliferative endometrium. Crypts in the cervix are also stimulated to produce fertile cervical mucus.This mucus reduces the acidity of the vagina, creating a more hospitable environment for sperm. It also has a characteristic texture that helps guide sperm through the cervix and to the fallopian tubes, where they wait for ovulation. In addition, basal body temperature may lower slightly under the influence of high estrogen levels

LH surge and ovulation

Estrogen levels are highest right before the LH surge begins. The short-term drop in steroid hormones between the beginning of the LH surge and the event of ovulation may cause mid-cycle spotting or bleeding. Under the influence of the preovulatory LH surge, the first meiotic division of the oocytes is completed. The surge also initiates luteinization of thecal and granulosa cells. Ovulation normally occurs 30 (± 2) hours after the beginning of the LH surge (when LH is first detectable in urine).

Follicular waves

The time from recruitment of tertiary stage follicles to ovulation is normally about two weeks, comprising days 1-14 of an idealized 28-day menstrual cycle. However, it is common for the follicular phase to last much longer, as sometimes no dominant follicle is selected. In this case, normally more tertiary stage follicles are recruited and the process begins again. One study of women with regular menstrual cycles found that none of them ovulated after the first wave of follicle development: 68% of cycles showed ovulation after the second wave, while 32% of cycles showed ovulation after the third wave.[12] Fertility awareness sources may refer to multiple waves of follicular development as a split peak because of the characteristic pattern of cervical mucus changes that is sometimes observed.

Assisted reproductive technology (ART) is a general term referring to methods used to achieve pregnancy by artificial or partially artificial means. It is reproductive technology used primarily in infertility treatments, otherwise known as 'fertility treatments'. Some forms of ART are also used in fertile couples for genetic reasons. ART is also used in couples who are discordant for certain communicable diseases, e.g. AIDS, to reduce the risk of infection when a pregnancy is desired. Examples of ART include in vitro fertilization, intracytoplasmic sperm injection (ICSI), cryopreservation, and intrauterine insemination (IUI). There is yet no strict definition of the term. Usage of the ART mainly belongs in the field of reproductive endocrinology and infertility.

	Definitions		Sweden
	Procedures		Canada
	Medication		Israel
	In vitro fertilization		New Zealand
	Others		Germany
	Risks		Ethics
	Usage		Fictional representation
	Costs		See also
	United States of America		References
	United Kingdom		External links

While there is no consensus on the definition, generally the process of intercourse is bypassed either by artificial insemination or fertilization of the oocytes in the laboratory environment (i.e., in vitro fertilization).

The Centers for Disease Control and Prevention (CDC) which is required as a result of the 1992 Fertility Clinic Success Rate and Certification Act to publish the annual ART success rates at U.S. fertility clinics defines ART to include "all fertility treatments in which both eggs and sperm are handled. In general, ART procedures involve surgically removing eggs from a woman's ovaries, combining them with sperm in the laboratory, and returning them to the woman's body or donating them to another woman." According to CDC, "they do not include treatments in which only sperm are handled (i.e., intrauterine or artificial insemination) or procedures in which a woman takes medicine only to stimulate egg production without the intention of having eggs retrieved

Procedures are mainly fertility medication, as well as ART techniques that use more substantial and forceful interventions, of which in vitro fertilization (IVF) and expansions of it (e.g. OCR, AZH, ICSI, ZIFT) are the most prevalent. However, there are also other manual ART, not necessarily dependent on IVF (e.g. PGD, GIFT, SSR).

Main article: Fertility medication

Most fertility medication are agents that stimulate the development of follicles in the ovary. Examples are gonadotropins and gonadotropin releasing hormone.

In vitro fertilization

Main article: In vitro fertilization

In vitro fertilization (IVF) is the technique of letting fertilization of the male and female gametes (sperm and egg) occur outside the female body.

Techniques usually used in in vitro fertilization include:

Intracytoplasmic Sperm Injection (ICSI)

Intracytoplasmic sperm injection (ICSI) is beneficial in the case of male factor infertility where sperm counts are very low or failed fertilization occurred with previous IVF attempt(s). The ICSI procedure involves a single sperm carefully injected into the center of an egg using a microneedle. This method is also sometimes employed when donor sperm is used.

Autologous endometrial coculture is a possible treatment for patients who have failed previous IVF attempts or who have poor embryo quality. The patient's fertilized eggs are placed on top of a layer of cells from the patient's own uterine lining, creating a more natural environment for embryo development.

In zygote intrafallopian transfer (ZIFT), egg cells are removed from the woman's ovaries and fertilized in the laboratory; the resulting zygote is then placed into the fallopian tube.

Cytoplasmic transfer is the technique in which the contents of a fertile egg from a donor are injected into the infertile egg of the patient along with the sperm.

Egg donors are resources for women with no eggs due to surgery, chemotherapy, or genetic causes; or with poor egg quality, previously unsuccessful IVF cycles or advanced maternal age. In the egg donor process, eggs are retrieved from a donor's ovaries, fertilized in the laboratory with the sperm from the recipient's partner, and the resulting healthy embryos are returned to the recipient's uterus.

Sperm donation may provide the source for the sperm used in IVF procedures where the male partner produces no sperm or has an inheritable disease, or where the woman being treated has no male partner.

Preimplantation genetic diagnosis (PGD) involves the use of genetic screening mechanisms such as Fluorescent In Situ Hybridization (FISH) or Comparative Genomic Hybridization (CGH) to help identify genetically abnormal embryos and improve healthy outcomes.

Embryo splitting can be used for twinning to increase the number of available embryos.

Surrogacy

Surrogacy via a gestational carrier is an option when a patient's medical condition prevents a safe pregnancy, when a patient has ovaries but no uterus due to congenital absence or previous surgical removal, and where a patient has no ovaries and is also unable to carry a pregnancy to full term.

Others

In gamete intrafallopian transfer (GIFT) a mixture of sperm and eggs is placed directly into a woman's fallopian tubes using laparoscopy following a transvaginal ovum retrieval.

Sex selection is the attempt to control the sex of offspring to achieve a desired sex. It can be accomplished in several ways, both pre- and post-implantation of an embryo, as well as at birth. Pre-implantation techniques include PGD, but also sperm sorting.

Artificial insemination (AI) is when sperm is placed into a female's uterus (intrauterine) or cervix (intracervical) using artificial means rather than by natural copulation. N.B. This can be a very low-tech process, performed at home by the woman alone or with her partner.

Conception devices, such as a conception cap are used to aid conception by enhancing[vague] the natural process. Conception caps are used by placing semen into a small conception cap, then placing the cap onto the cervix. This holds the semen at the cervical os, protecting the semen from the acidic vaginal secretions and keeping it in contact with the cervical mucus.

Artificial insemination by donor is used in situations where the woman doesn't have a partner with functional sperm. Instead, a sperm donor supplies the sperm.
Surrogacy, where a woman agrees to become pregnant and deliver a child for a contracted party. It may be her own genetic child, or a child conceived through natural insemination, in vitro fertilization or embryo transfer using another woman's ova.

Reproductive surgery, treating e.g. fallopian tube obstruction and vas deferens obstruction, or reversing a vasectomy by a reverse vasectomy.

In surgical sperm retrieval (SSR) the reproductive urologist obtains sperm from the vas deferens, epididymis or directly from the testis in a short outpatient procedure.

By cryopreservation, eggs, sperm and reproductive tissue can be preserved for later IVF.

Risks

The majority of IVF-conceived infants do not have birth defects.[3] However, some studies have suggested that assisted reproductive technology is associated with an increased risk of birth defects.[4][5] In the largest U.S. study, which used data from a statewide registry of birth defects,[6] 6.2% of IVF-conceived children had major defects, as compared with 4.4% of naturally conceived children matched for maternal age and other factors (odds ratio, 1.3; 95% confidence interval, 1.00 to 1.67).

The main risks are:
Genetic disorders. DNA damage increases in e.g. IVF and ICSI, which is reflected e.g. by upregulation of the gene expression of HNRNPC in the placenta.

Low birth weight. In IVF and ICSI, a risk factor is the decreased expression of proteins in energy metabolism; Ferritin light chain and ATP5A1.

Preterm birth. Low birth weight and preterm birth are strongly associated with many health problems, such as visual impairment and cerebral palsy, and children born after IVF are roughly twice as likely to have cerebral palsy.

Other risk factors are:
Membrane damage, which is contributed to or reflected by increased expression of the membrane fusion proteins NAPA and Annexin A3.

Sperm donation is an exception, with a birth defect rate of almost a fifth compared to the general population.[9] It may be explained by that sperm banks accept only people with high sperm count.

Current data indicate little or no increased risk for postpartum depression among women who use ART.

Usage
Assisted reproductive technology procedures performed in the U.S. has more than doubled since 10 years ago, with 140.000 procedures in 2006,[11] resulting in 55.000 infants born.

In Australia, 3.1% of babies now born are a result of ART.

In case of discontinuation of fertility treatment, the most common reasons have been estimated to be: postponement of treatment (39%), physical and psychological burden (19%, psychological burden 14%, physical burden 6.32%), relational and personal problems (17%, personal reasons 9%, relational problems 9%), treatment rejection (13%) and organizational (12%) and clinic (8%) problems.

Costs

Not everyone in the U.S. has insurance coverage for fertility investigations and treatments. Many states are starting to mandate coverage, and the rate of utilization is 277% higher in states with complete coverage.[14]

There are some health insurance companies that cover diagnosis of infertility but frequently once diagnosed will not cover any treatment costs.

2005 approximate treatment/diagnosis costs (United States, costs in US$):

Initial workup: hysteroscopy, hysterosalpingogram, blood tests ~$2,000

Intrauterine Insemination (IUI) aka Artificial insemination ~ $200– 900 per. trial

Sonohysterogram (SHG) ~ $600 – 1,000

Clomiphene citrate cycle ~ $ 200 – 500

IVF cycle ~ $10,000 -30,000

Use of a surrogate mother to carry the child dependent on arrangements

Another way to look at costs is to determine the expected cost of establishing a pregnancy. Thus if a clomiphene treatment has a chance to establish a pregnancy in 8% of cycles and costs $500, the expected cost is $6,000 to establish a pregnancy, compared to an IVF cycle (cycle fecundity 40%) with a corresponding expected cost of $30,000 ($12,000/.4).

For the community as a whole, the cost of IVF on average pays back by 700% by tax from future employment by the conceived human being.

United Kingdom

In the UK all patients have the right to preliminary testing, provided free of charge by the National Health Service. However, treatment is not widely available on the NHS and there can be long waiting lists. Many patients therefore pay for immediate treatment within the NHS or seek help from private clinics

Sweden

In Sweden, official fertility clinics provide most necessary treatments and initial workup, but there are long waiting lists, especially for egg donations, since the donor gets just as low reward as the receiving couple are charged. However, there are private fertility clinics.[citation needed]

Canada

See also: Assisted Human Reproduction Act

Some treatments are covered by OHIP (public health insurance) in Ontario and others are not. Those undergoing artificial insemination or with bilaterally blocked fallopian tubes and under 40 have treatment is covered but are still required to pay lab fees (around $3,000–4,000). Coverage varies in other provinces. Most other patients are required to pay for treatments themselves.

Israel

Israel's National Health Insurance, which is mandatory for all Israeli citizens, covers nearly all fertility treatments. In-Vitro-Fertilization costs are fully subsidized up to the birth of two children for all Israeli women, including single women and lesbian couples. Embryo transfers for purposes of gestational surrogacy are also covered.

New Zealand

The national public health system of New Zealand covers IVF treatment in specific circumstances only, based on a 'points for conception challenges' equation.[citation needed] Publicly funded IVF treatments are limited (between one and three treatments dependent on criteria) and are subject to substantial wait-lists, dependent on local health funding region, which raises potential inequity of ART support across the country.[citation needed] Infertility testing through blood tests can be covered by public funding, however in the absence of explicit gynecological complications, additional investigations are may not be covered publicly. Investigation such as a hysterosalpingogram may be covered, but the wait-list could be in excess of six weeks, whereas a privately sourced HSG can cost $NZ900 but is readily available. Many New Zealanders select self-funded IVF cycles, at approximately $NZ10,000 per cycle, and other forms of ART, such as IUI, at approximately $NZ1200, using the services of private fertility clinics, which in itself is a growing local industry. Individuals using private services are generally not covered under personal health insurance policies in New Zealand.

Germany

On 27 January 2009, the Federal Constitutional Court ruled that it is unconstitutional, that the health insurance companies have to bear only 50 percent of the cost for in vitro fertilization.[19] On 2 March 2012, the Federal Council has approved a draft law of some federal states, which provides that the federal government provides a subsidy of 25 percent to the cost. Thus, the share of costs borne for the pair would drop to just 25 percent.

Ethics

Some couples find it difficult to stop treatment despite very bad prognosis, resulting in futile therapies. This may give ART providers a difficult decision of whether to continue or refuse treatment.


For treatment-specific ethical considerations, see entries in individual subarticles, e.g. In vitro fertilisation, Surrogacy and Sperm donation
[edit]Fictional representation

Films and other fiction depicting emotional struggles of assisted reproductive technology have had an upswing in the latter part of the 2000s decade, although the techniques have been available for decades.Yet, the amount of people that can relate to it by personal experience in one way or another is ever growing, and the variety of trials and struggles are huge.

For specific examples, refer to the fiction sections in individual subarticles, e.g. surrogacy, sperm donation and fertility clinic.

In addition, reproduction and pregnancy in speculative fiction has been present for many decades.

The Fertility Chase (medical documentary series)
Religious response to ART
Sperm donation
Sperm bank
Artificial uterus
Human cloning
Diethylstilbestrol
Spontaneous conception, the unassisted conception of a subsequent child after prior use of assisted reproductive technology

Intrauterine insemination (IUI) is a procedure that involves placing sperminside a woman’s uterus to facilitate fertilization. This fertilitytreatment does not involve the manipulation of a woman’s eggs, andtherefore is not considered an assisted reproductive technology (ART) procedure

Findan Infertility Specialist in Your Area

Get Your Free journal, forums,& more

What is IUI?

IUI is a fertility treatment that uses a catheter to place a numberof washed sperm directly into the uterus. The goal of IUI is to increasethe number of sperm that reach the fallopian tubes and subsequentlyincrease the chance of fertilization.

When is IUI used?

IUI is a fertility treatment often selected by couples who have been tryingto conceive for at least one year with no success. IUI may be selected asa fertility treatment with any of the following conditions:

Unexplained infertility
Low sperm count
Decreased sperm mobility
Requirement of donor sperm
A hostile cervical condition, such as cervicalmucus that is too thick
Cervical scar tissue from past procedures or endometriosis
Ejaculation dysfunction

IUI provides the sperm an advantage by giving it a head start, but stillrequires a sperm to reach and fertilize the egg on its own

How does IUI work?

The IUI procedure is simple and may be performed even if the woman is notreceiving medication to improve her egg production. Many physicians willencourage women to take medications to stimulate the ovaries to increaseegg production in order to improve the chance of achieving pregnancy.

An ultrasound will be used to monitor the size of the follicles (folliclesdevelop into eggs). The hormone, human Chorionic Gonadotropin (hCG), isadministered to stimulate the release of eggs from the follicles.

A semen sample will be washed by the lab to separate the semen from theseminal fluid. A catheter is used to inject the processed sperm directlyinto the uterus. This process maximizes the number of sperm cells that areplaced in the uterus, thus increasing the possibility of conception. TheIUI procedure takes little time and involves minimal discomfort. The nextstep is to watch for signsand symptoms of pregnancy.

Women under the age of 35 usually have higher rates of success than womenover age 35, but the average success rate for IUI ranges from 10-20% inone cycle. With IUI, as with other methods of artificial insemination, thesuccess rate depends primarily on the health of both the sperm and the woman.