Treatment of Infertility

TREATMENT

A couple’s infertility may be related to one or several abnormalities in one or both partners. Numerous medical,surgical, and assisted reproductive technology (ART) ther-apies are available for treating the infertile couple. For coupleswith unexplained infertility, empiric treatment may over-come the negative effects of one or more mild abnormal-ities. These couples, as well as the majority of infertile couples, tend to proceed through fertility treatment in a stepwise fashion, starting with conservative and then with more aggressive ovarian stimulation, inseminations, and eventually proceeding to IVF (explained below).

Surgical procedures are indicated in certain circum-stances. If a woman presents with pelvic pain and infertility, laparoscopy may be used to identify and treat the cause of her pelvic pain as well as evaluate pelvic anatomy from a fer-tility standpoint. If an obstructed fallopian tube is identified with HSG, it may be possible to correct the obstruction sur-gically. For these operations to be successful, the endo-salpinx must be healthy. If the tubal damage is significant enough to impair gamete transport, then an ART such as IVF may be necessary. When indicated, abnormalities of the uterine cavity such as submucosal leiomyomas, endometrial polyps, intrauterine adhesions, and a septum can be surgically corrected with a hysteroscopic procedure.

Ovarian Stimulation

Ovulation induction is indicated in women with anovula-tion or oligo-ovulation. However, any identified condition asso-ciated with ovulatory disorders should be treated before initiating ovulation-induction therapy. Such conditions include thyroid dis-orders, hyperprolactinemia, PCOS, and high levels of stress (including psychologic stress, intense exercise, or eating disorders).

The most commonly used medication for ovulation induction is clomiphene citrate.Clomiphene is a selective estrogenreceptor modulator (SERM) that competitively inhibits estrogen binding to the estrogen receptors at the hypothal-amus and pituitary. The anti-estrogen effects of clomiphene induce gonadotropin release from the pituitary, which stim-ulates follicle development in the ovaries. Clomiphene is administered daily for 5 days in the follicular phase of the menstrual cycle, starting between cycle days 3 to 5. If ovula-tion does not occur, the dose is increased for the subse-quent month. Women with ovulatory disorders associated with oligomenorrhea may not have regular menses and may require a progesterone-induced menses to start their clomiphene cycle. When used in women who are already ovulatory, clomiphene may stimulate development of sev-eral mature follicles.

With clomiphene, ovulation can occur between 5 to 12 days after the last pill, and it can be monitored in several ways. Urine LH kits can be used each day starting on cycle day 10; when ovulation occurs, exposure to sperm through intercourse or intrauterine insemination (IUI) should occur. Transvaginal ultrasound performed on cycle day 11 or 12 may identify a developing follicle. When ultrasound is used and a mature follicle is identified (average diameter >18 mm), ovulation can be triggered by administering a sub-cutaneous injection of hCG. The exogenous hCG effec-tively simulates the LH surge and ovulation occurs; this practice enables the proper timing of intercourse or insem-ination. Some couples prefer to not monitor ovulation, and have regular midcycle intercourse. In this situation, a serum progesterone level on cycle day 21 can identify if ovulation has occurred. The use of clomiphene is associated with a 10% riskof multiple gestations, the majority of which are twin gestations, and a small risk of ovarian hyperstimulation and cyst formation.

Alternatively, exogenous gonadotropins can be given to stimulate follicular development. The use of gonado-tropins is commonly referred to as controlled ovarianhyperstimulation (COH). This therapy aims to achievemonofollicular ovulation in anovulatory women (particu-larly those who do not respond to clomiphene), and ovula-tion of several mature follicles in other infertile women. Available preparations include purified human menopausal gonadotropins (FSH and LH are extracted from the urine of postmenopausal women), and recombinant human FSH. The dose of medication is tailored to a woman’s age, body weight, infertility diagnosis, and response to previous fer-tility treatments. These medications are more potent than clomiphene and require frequent monitoring of follicle growth that usually includes transvaginal ultrasonography and serum estradiol measurements. When at least one mature follicle is identified (average follicle diameter of 18 mm and serum estradiol concentration >200 pg/mL), hCG is administered to trigger ovulation. Timed insemina-tions are commonly performed within 12 to 36 hours from hCG administration. The risks of this therapy include ovarian hyperstimulation syndrome (OHSS), which can require intensive therapy; a 25% incidence of multiple gestations; and an increased risk of ectopic pregnancy. 

Intrauterine Insemination

Before performing IUI, an ejaculated semen specimen is washed to remove prostaglandins, bacteria, and proteins. The sperm is then suspended in a small amount of medium To perform IUI, a speculum is inserted into the vagina, the specimen is placed in a thin flexible catheter, and the catheter is advanced through the cervix into the uterine cavity where the specimen is deposited (Fig. 38.7). A total motile sperm count (concentration multiplied by motility) of at least one million must be present, as pregnancy is rarely achieved with lower counts. In couples with infertility,and particularly in those with mild male infertility, pregnancy rates are increased with IUI. However, more severe maleinfertility may necessitate the use of ART to achieve preg-nancy. If the male partner is azoospermic and no sperm are identified during testicular biopsy, or if a woman does not have a male partner, IUI with anonymous donor sperm is an available alternative.

Assisted Reproductive Technologies

All fertility procedures that involve manipulation of gametes, zygotes, or embryos to achieve conception com-prise the assisted reproductive technologies (ART). In the United States, IVF accounts for more than 99% of all ART procedures. The process of IVF involves ovarian stimulation toproduce multiple follicles, retrieval of the oocytes from the ovaries, oocyte fertilization in vitro in the laboratory, embryo incuba-tion in the laboratory, and transfer of embryos into a woman’s uterus through the cervix. The required medications for IVFinclude gonadotropins to stimulate follicle development, a gonadotropin-releasing hormone analogue (agonist or antagonist) to prevent premature ovulation during folli-cle development, and hCG to initiate the final matura-tion of oocytes prior to their retrieval. As with COH, the IVF process necessitates careful monitoring of ovarian response with transvaginal ultrasonography and serum estradiol measurements.

Depending on the etiology of infertility, fertilization can be achieved “naturally” by placing tens of thousands of sperm together with a single oocyte, or with intracyto-plasmic sperm injection (ICSI) by which a single spermis injected directly into the oocyte (Fig. 38.8).  

Therefore, IVF provides the tools necessary to bypass the normal mechanisms of gamete transport, fertilization, and embryo transport. After oocyte retrieval, daily progesterone supplemen-tation is necessary to insure the appropriate secretory changes in the endometrium and to support the potential pregnancy; if con-ception occurs, supplementation is continued until at least 10 weeks of gestation.

Indications for IVF include the following: absent or blocked fallopian tubes, tubal sterilization, failed surgery to achieve tubal patency, severe pelvic adhesions, severe endometriosis, poor ovarian response to stimulation, oligo-ovulation, severe male factor infertility, unexplained infertility, or failed treatment with less aggressive therapies. Success rates with IVF depend on the etiology of infertility and the age of the female partner. The chance of conception withone IVF cycle depends on the number and quality of embryos transferred, and can be as high as 40% to 50%, with a 30% rate of multiple gestations and at least a 15% rate of spontaneous abortion.