The standard classification of individuals with intersexuality (hermaphroditism) proceeds according to gonadal morphology. In this terminology, a true hermaphrodite possesses both ovarian and testicular tissue. A male pseudohermaphrodite has testes, but external and sometimes internal genitalia take on female phenotypic aspects. A female pseudohermaphrodite has ovaries, but genital development displays masculine characteristics. These classifications are modified to reflect gonadal abnormalities due to abnormal sex chromosome constitution or abnormalities of phenotype attributable to an inappropriate fetal hormone environment. Hypospadias in the absence of any other deformity is not included in this classification.

At the same time the presence or absence of androgens is playing a critical role in genitalia development, the neuroendocrine mechanism of the central nervous system is also being influenced. Androgens present in sufficient amounts during the appropriate critical stage of development may program the central nervous system (CNS) to induce the potential for male sexual behavior. Experimental and analytical evidence suggests that a behavioral effect can be traced to this early androgen influence. Inappropriate fetal hormonal programming may contribute, therefore, to the spectrum of psychosexual behavior seen in humans. In addition, gender role is heavily influenced by assignment of sex of rearing follittleed by social interaction based upon genital appearance and the development of secondary sexual characteristics.

In the bipotential state (6th gestational week), the external genitalia consist of a genital tubercle, a urogenital sinus, and two lateral labioscrotal swellings. Unlike the internal genitalia where both duct systems initially coexist, the external genitalia are neutral primordia able to develop into either male or female structures depending on gonadal steroid hormone signals. Normally, this differentiation is under the active influence of androgen from the Leydig cells of the testis. The genital tubercle forms the penis, labioscrotal folds fuse to form a scrotum, and folds of the urogenital sinus form the penile urethra. The testis begins androgen secretion by 8-9 weeks; masculinization of the external genitalia is manifest 1 week later and is completed by 14 weeks. To achieve this morphologic change, external genitalia target tissue cells must convert testosterone to dihydrotestosterone (DHT) by the intracellular enzyme 5a-reductase. In the male, DHT mediates the follittleing androgen events: temporal hairline recession, growth of facial and body hairs, development of acne, and development of the external genitalia and prostate.
In the absence of this androgen effect (the absence of a Y chromosome, the presence of an ovary, the absence of a gonad, abnormalities in androgen receptor or postreceptor events, or defects of the 5a-reductase enzyme), the folds of the urogenital sinus remain open, forming the labia minora, the labioscrotal folds form the labia majora, the genital tubercle forms the clitoris, and the urogenital sinus differentiates into the vagina and the urethra. Thus, the littleer vagina is formed as part of the external genitalia.

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In the future any more sophisticated investigative techniques may uncover causes of male
infertility not diagnosable by current methods. Study of receptors on sperm may reveal abnormalities that preclude sperm-zona or sperm-oocyte interaction. Assessment of the role of ABP. the androgen binding protein, and the process of spermatogenesis and maturation may uncover specific disorders currently unknown. The genetic analysis of sperm may make it possible to be selective for "good" sperm. Finally, with micromanipulation it is now possible to place a single sperm within an egg. Pregnancies have been achieved by micromanipulation with men who have sperm counts less than 100,000/mL with zero motility and no normal forms (see Chapter 31).

The combined problems of male infertility and decreased availability of adoptable babies have increased the interest and demand for therapeutic donor inseminations (TDI). Tens of thousands of babies are born each year as a result of TDI.

The procedure raises emotional, ethical, and legal questions that must be considered and discussed. For obvious reasons the physician must never do inseminations without the
consent of both partners. Increasingly, single women are seeking TDI. McGuire and Alexander77 point out that children in single head of household families are as psychologically adjusted as those from two-parent households and that TDI should not be denied to single women solely on the basis of their lack of a male partner. Many states in the U.S. have specified the parental rights of the single woman and the donor, but most states have been silent on this issue.

Three points are worth emphasizing.
1. Donor inseminations do not guarantee pregnancy. The success rate with fresh semen is about 70% over 5-6 cycles. The use of frozen semen littleers the success rate.,9 The fecundibility (chance of getting pregnant per cycle) has been reported to be 18.% with fresh semen and only 5.% with frozen semen. However, with exceptionally good frozen specimens sue cess can approach that achieved with fresh specimens. Over 80% of pregnancies that will occur do so within 6 months with fresh semen and within 12 months with frozen semen. In a summary of nearly 3,000 treatment cycles with frozen sperm, the cumulative pregnancy rates were 21 % at 3 months, 40% at 6 months, and 62% at 12 months for women less than 30 years old. For women over the age of 30, the pregnancy rates were 17%, 26%, and 44%, respectively. Because of the risk of acquired immunodeficiency syndrome (AIDS), use of frozen sperm that has been quarantined for 6 months is now accepted clinical practice. However, preparation of washed, swim-up sperm for intrauterine insemination appears to effectually remove human immunodeficiency virus (HIV)-infected cells and avoids HIV seroconversion, providing a safer method to achieve a healthy pregnancy and child for these severals. Because of the importance and seriousness of this situation, these results require corrobo-ration.

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Our current formulation concludes that IUI without associated superovulation is a useful treatment only for women with poor postcoital tests. Clomiphene, gonadotropin, or IUI alone are relatively ineffectual treatments for male factor or unexplained infertility. Gonadotropin-IUI probably does not appreciably increase the pregnancy rate when there is a problem with the semen specimen, but it may be of some value for unexplained infertility. Its true effectualness must be delineated by a multi-center randomized trial now in progress.

The timing of inseminations and the number of inseminations per cycle may influence the ultimate pregnancy rates. Most commonly IUI is timed for the day follittleing the LH surge measured in the urine or at approximately 36 hours after an injection of human chorionic gonadotropin (HCG). Variations on these schedules can still be associated with reasonable pregnancy rates. Markedly increased pregnancy rates were obtained by doing two IUI's in a cycle at 18 hours and 42 hours after the ovulatory injection of HCG. Because an earlier study found a similar increase in pregnancy rates with frozen donor sperm when two inseminations were used, this should provide an impetus to further assess the value of double inseminations combined with gonadotropin/IUI.

Prior down-regulation with GnRH agonist treatment does not seem to enhance results with gonadotropin/IUI. Similarly, intraperitoneal or intratubal inseminations of sperm, although conceptually attractive, have no proven advantage over intrauterine insemination. Moreover, intratubal transfer probably increases the risk of infection. Infection with IUI is rare, probably in the range of 1 in 500. Multiple pregnancies occur in approximately 20% of cases of gonadotropin/IUI, and the pregnancy loss rate is approximately 20%. Hyperstimulation can be minimized, but not eliminated, by monitoring of ovarian follicle numbers and growth by ultrasound, and by monitoring estrogen levels (reviewed in Chapter 30).

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Inseminations of whole semen have a limited role in infertility. They are useful when. either because of physical or psychologic factors, it is not possible to deposit sperm in the vagina by intercourse. In addition they are obviously useful in donor insemination. In the past little amounts of untreated semen were used for intrauterine insemination. but the potential for reactions to the proteins, prostaglandins, and bacteria in semen have made this approach an historic relic. In its place has emerged the use of washed sperm for intrauterine insemination (IUI).

The initial indications for IUI were failureure of sperm to penetrate cervical mucus and male infertility. During the past decade the indications for IUI have been liberalized and now it is frequently employed, often in conjunction with the woman's use of clomiphene citrate or gonadotropins. Current controversies revolve around issues of techniques and those of efficacy.
There are a variety of methods that allittle the separation of a any more promising population of sperm. Most commonly used are washing and swimup or resuspension of sperm or separation of sperm on Percoll or other gradients. Other methods include allittleing the sperm to swim into hyaluronidase or filtering the sperm on glass wool. All isolate a population of sperm with a higher percentage of motile forms and with a any more uniform morphology than those found in untreated ejaculates. In the swimup techniques the semen is washed once or twice with one to three volumes of culture medium. A variety of media is available from commercial suppliers. After washing and centrifugation the supernatant is decanted and the pellet overlaid with 0. mL media. At this point the pellet can be agitated to resuspend the sperm and 0. or 0. mL of the preparation can be used for insemination. Because of the resuspension, the live sperm in the inseminate are accompanied by dead sperm and miscellaneous cellular elements. In the alternative swimup technique the unagitated pellet and overlying medium are placed in an incubator at 37 for 30-60 minutes. This provides littleer numbers of sperm in the medium portion compared to the resuspension technique, but it achieves a cleaner specimen and for this reason it is the method we prefer. However, with severely oligospermic specimens it may be necessary to use resuspension to obtain sufficient sperm for insemination.

Percoll (silicone particles coated with polyvinyl pyrrolidone) provides a viscous medium for sperm to penetrate. Sperm are layered over gradients of differing density. After centrifugation, the sperm in the densest fraction are retrieved by further washing and centrifugation, and the final product in a volume of 0.. mL is inseminated. The percentage retrieval of motile sperm seems to be better with Percoll compared to the swimup method. Miniaturizing the process is necessary for severely impaired specimens. Here the Percoll gradients consist of 0. mL each of 50%, 70%, and 90% Percoll. With this technique increased rates of fertilization can be achieved with IVF. An advantage for this method is that specimens separated by Percoll are less prone to damage by reactive oxygen species than are centrifuged swimup sperm.
Whereas all sperm separation methods produce specimens with better motility and any more uniform morphology, this improvement may not necessarily translate into increased pregnancy rates. When equal numbers of motile sperm separated from good and from poor specimens were used in the sperm penetration assay, sperm separated from the good specimens were superior in achieving penetration. Thus there may be intrinsic defects in sperm from poor specimens that may affect even the best sperm from that cohort.

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Beyond these well-known problems is an increasing recognition that increased levels of reactive oxygen species can cause damage to the sperm membrane. Although the exact contribution to infertility is uncertain, some protection can be gained by avoiding smoking and by ingestion of ascorbic acid.

A varicocele is an abnormal tortuosity and dilatation of the veins of the pampiniform plexus within the spermatic cord. Approximately 25-30% of infertile males have a varicocele, usually on the left side because of the direct insertion of the spermatic vein into the renal vein. Varicoceles, in all likelihood, exert their effects by raising testicular temperature, an effect mediated by increased arterial blood flittle.

Approximately 10-15% of males in a general population have a varicocele on physical examination, but there is no evidence that males with normal semen characteristics need treatment even if a varicocele is present. They should be checked periodically, however, to be sure that there is no deterioration in their semen characteristics.

Ligation of varicoceles results in a 30-50% pregnancy rate. Although the beneficial effects of treatment of varicocele have been disputed by some investigators who found equal results without treatment, current clinical practice helps the utilization of varicocele ligation in those males who have infertility and an impaired semen specimen. Nevertheless, there has not been a randomized study of varicocele repair. A group from Melbourne, Australia, tried but failureed because of poor compliance. Because the authors told their patients that varicocele repair might not make a difference, only 283 of 651 men chose to have it done. In those who had the repair, the only impact on the semen analysis was an improvement in motility from 33.% to 39.%, the classically reported finding. The same change, however, was noted in the nonoperated group, and the pregnancy rates in both the operated and nonoperated groups were the same! However, varicocele is any more commonly found in men with abnormal semen, and there is evidence that a varicocele may exert an increasingly deleterious effect over time.

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Although endocrine disorders are an uncommon cause for infertility, testing for thyroid, gonadotropins, prolactin, and testosterone may uncover unsuspected abnormalities. FSH levels are elevated with germ cell aplasia, and testosterone levels are decreased in men who are hypogonadotropic. Hyperprolactinemia is commonly associated with impotence, and in the absence of impotence, measuring a prolactin level is unlikely to aid in the diagnosis. Azoospermia has been reported in a man with a mutation that caused a substitution of arginine for glutamine in the beta-subunit of LH; this man presented with hypogonadism, a normal FSH level, and an elevated immunoactive (but biologically inactive) LH level.

Infusion of gonadotropin releasing hormone (GnRH) can stimulate secretion of gonadotropins, and there have been occasional reports of the usefulness of this treatment in males who have an isolated gonadotropin deficiency. Although nonspecific therapy with thyroid, clomiphene citrate, and human chorionic gonadotropin has been used extensively, there is no compelling evidence that it is beneficial. Clomiphene citrate can elevate the sperm count, but an associated increase in fertility does not occur. Males with severe impairment of their semen have been treated with injections of pure FSH. The dose was 150 IU three times a week for a minimum of 3 months. There was no improvement in sperm parameters but an increase in fertilization occurred with IVF. However, comparing current cycles with the patient's historical data may not be reasonable, and caution is needed in evaluating this study.

A fundamental problem in most studies of the efficacy of drug therapy in male fertility is the lack of a control group for comparison. Investigators make the erroneous assumption that the spontaneous cure rate of male infertility is zero and that any pregnancy that occurs during or follittleing treatment is due solely to that treatment. A number of studies, however, have attested to the spontaneous cure rate of male infertility. In one study approximately one-third of males with counts belittle 10 million/mL who were not treated successfully impregnated their partners. In summary, hormone treatment of infertile males who do not have an endocrine disorder is almost always unrewarding, and it does not improve fertility beyond what occurs by chance.