Nuclear medicine in problems of fertility and impotence

Nuclear Medicine in Problems of Fertility and Impotence Lionel S. Zuckier and Mark D. Strober Nuclear medicine techniques may be used t o t e s t fallopian tube patency and penile vascular inflow and o u t f l o w . Radionuclide hysterosalpingography (HSP) is a readily performed method of evaluating fallopian t u b e patency, and is believed to be more physiologic and functionally informative than the accepted radiologic method of contrast HSP. The test is simple t o perform and interpret and offers an accurate alternative to the contrast examination. For scintigraphic evaluation of impotence, blood pool studies are most useful in assessing the integrity of arterial inflow, but

may also be used to generate indices of venous leak. Washout of xenon after subcutaneous injection, in t h e flaccid state, has been used as a measure of baseline penile perfusion, as has intracavernosal injections in the flaccid penis. Intracavernosal xenon washout during erection seems the most useful method of testing venous integrity. Washout using technetium-99m (m"Tc)-Iabeled red blood cells (~"Tc.RBC) may emerge as a convenient alternative t o the more technically difficult xenon examinations. Copyright 9 1992 by W.B. Saunders Company

is a widespread condition afI NFERTILITY fecting as many as 15% of couples. Al-

evaluate uterine and tubal anatomy. Assessment of tubal patency can also be addressed by monitoring spillage of contrast into the peritoneum. Contrast HSP is nonphysiologic in that contrast is introduced through the cervix under positive pressure, potentially demonstrating tubal patency, which may not usually be present or which may not be relevant to the normal physiologic mechanisms of transport of sperm. Other limitations of this radiologic study include patient discomfort and possible hypersensitivity to iodinated contrast media. Radionuclide HSP, although lacking the anatomical resolution of the radiographic contrast examination, is less invasive and provides more functional and physiologic imaging. Additionally, patient discomfort is minimized and hypersensitivity reactions are avoided.

though an exact gender contribution is unknown, it has been estimated that males and females each account for at least one third of cases, while in the remaining third, important abnormalities may be present in both sexes. 1 This report reviews current radionuclide procedures used to functionally image the male and female reproductive systems. The scintigraphic evaluation of male impotence has been covered recently in an earlier Seminars. 2 This review updates that and focuses on the historical and conceptual basis of these examinations, highlighting recent advances in this developing area. The scintigraphic analysis of female disorders was reviewed in Seminars some 11 years a g o . 3 The use of radioimmunoassay (RIA) to evaluate hormonal levels, an important in vitro examination in infertility, will not be covered. FALLOPIAN TUBE PATENCY AND FUNCTION

Fallopian tube abnormalities account for a high percentage of fertility problems in women and confirmation of tubal patency is an essential component of the workup of this problem. Contrast hysterosalpingography (HSP), the standard radiologic procedure for this purpose, provides the spatial resolution necessary to From the Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, NY. L.S.Z. is the recipient of Physician Scientist Award No. 1Kll CA01503. Address reprint requests to Lionel S. Zuckier, MD, Albert Einstein College of Medicine, Department of Nuclear Medicine, 1300 Morris Park Ave, Bronx, N Y 10461. Copyright 9 1992 by W.B. Saunders Company 0001-2998/92/2202-0006505.00/0 122

Uterine Anatomy

A brief synopsis of female pelvic anatomy and relevant physiology is in order. The uterus is composed of a thick layer of smooth muscle (myometrium) and a hormonally dependent endometrial lining. The pear-shaped uterus is divided into the fundus superiorly, the body below and the cervix inferiorly. The upper third of the vagina encuffs the cervix, thereby creating the anterior, posterior, and lateral fornices. The uterine or fallopian tubes join the uterine fundus at both superolateral aspects and extend outwards in the broad ligament toward the ovaries. The fallopian tube has been anatomically divided into a uterine or interstitial portion, a short and narrow isthmus, a long and somewhat dilated region known as the ampulla, and a fimbriated terminal portion known as the infundibulum. Seminars in Nuclear Medicine, Vol XXII, No 2 (April), 1992: pp 122-137

FERTILITY AND IMPOTENCE

123

Fertilization normally occurs in the ampullary portion of the fallopian tubes, requiring arrival of both sperm, initially deposited near the external os of the cervix, and an ovum, released from the ovary adjacent to the fallopian tube infundibulum. The movement of sperm from the vagina, through the uterus and into the fallopian tube, is thought to be principally due to vaginal and uterine muscular contractions, while movement of the ovum within the fallopian tube is believed to be caused by ciliary action of the ciliated columnar epithelium. While the mechanisms of sperm and ovum transport are not fully understood, it is evident that both anatomic and functional requirements must be met for normal fertilization to take place. Radionuclide Studies

Feasibility of radionuclide HSP was initially suggested by Iturralde and Venter who investigated retrograde migration of radioactive particulate substances from the vagina through the uterus to the ovaries. 3 In patients undergoing gynecologic surgery, 10 mCi of technetium-99m (99mTC) human albumin microspheres (HAM) were instilled at the posterior fornix of the vagina and retrograde migration of particles was conclusively demonstrated by in vitro counting of uterine and adnexal specimens. Although the aim of these studies was to demonstrate the potential movement of suspected carcinogens such as asbestos and talc from the vagina to the ovary, visualization of the upward migration of the 10- to 35-1xm particles suggested an imaging procedure to assess tubal patency. Utility of this technique as an imaging modality was investigated by the examination of a second group of patients referred from an infertility clinic (Table 1). Following the deposition of 2 to 3 mCi of [99mTc]HAM at the pos-

terior fornix of the vagina or adjacent to the external os, patients were imaged at 1, 2, 3, and 24 hours in the anterior projection using a large field of view (LFOV) gamma camera and lowenergy, all-purpose (LEAP) collimator. Studies were interpreted as abnormal if activity was not visualized in one or both of the fallopian tubes and especially if no activity collected in the region of the fimbria. Agreement between the radionuclide procedure and confirmatory contrast HSP and peritoneoscopy was found in 21 patients. Five studies were interpreted as tubal nonpatency on the radionuclide scan, but patency on the comparison studies. The investigators accounted for these seemingly false-positive studies by suggesting that the introduction of contrast or dye under high pressures may erroneously create an impression of patency. In another patient, with vaginal septum and double uterus, unilateral tubal patency was observed on radionuclide examination, but not on HSP or peritoneoscopy. Here too, it was believed that the scintigraphic procedure provided the correct diagnosis, because the correlative examinations were technically limited due to the variant anatomy. These investigators concluded that the radionuclide procedure was more indicative of the functional state of the fallopian tubes than contrast HSP. McCalley et al, in a prospective study of 26 patients referred from an infertility clinic, introduced several procedural modifications, including reduction of the administered dose to 1 mCi4 (Table 1). Another report by the same group described a slightly expanded series, with similar results. 5 The radiotracer was suspended in 1 mL saline and placed directly onto the cervical mucosa. A nonabsorbent tampon was placed in the vagina to prevent leakage, and the patient was then walked to the Department of Nuclear Medicine for imaging. Anterior pelvic images

Table 1. Radionuclide HSP Studies and Their Comparison With Correlative Examinations Disagree*

Investigator

Dose (mCi)

Volume (mL)

Total No. of Patients

Agree

RH+, CE-

RH-, CE+

Iturralde 3 McCalley 4 Angtuaco e

2-3 1 1

<1 1 NS

29 26 13

54 52 20

48 49 16

5(5) 2(2) 4(2)

1(1) 1(0) 0

Overall

--

--

68

126

113

11 (9)

2(1 )

Tubes Studied

Abbreviations: RH, radionuclide HSP; CE, correlative examinations; +, abnormal; - , normal; NS, not specified. *Numbers in parentheses indicate discrepant cases where RH judged correct.

124

ZUCKIER AND STROBER

were obtained 15 to 30 minutes later by gamma camera using pinhole collimation and caudal angulation to maximize separation of the region posterior to the uterus (Fig 1). Lateral obliques were also obtained when needed. Imaging was terminated when bilateral tubal patency was demonstrated, or after 1~/2to 489hours, depending on the willingness of the patient to stay for delayed views. Patency of a fallopian tube was inferred if a relatively intense focus of activity was imaged in the area of the adjacent adnexa. If no such activity was seen on images 1 or more hours after radiotracer administration, then that tube was considered obstructed. These investigators coined the term "cornu cutoff sign" for a discontinuity of activity from the region of the cornu to the ipsilateral fallopian tube (Fig 2). Direct observations of surgical pathology, peritoneoscopy, and contrast HSP were used as comparison studies. Among the 52 tubes studied by this method, there was agreement between the radionuclide and correlative studies in 34 patent and 15 obstructed tubes. Two tubes were obstructed on the radionuclide study, but were judged patent

by correlative examinations. At surgery, these tubes were described as immotile with peritubal and periadnexal adhesions that most likely rendered them functionally incapable of transport of particles. One tube was patent by the radionuclide procedure, but found to be obstructed at surgery. The investigators attribute this case to misinterpretation of the scintigraphic examination due to cross-over of radionuclide spillage from the contralateral patent tube. In virtually all cases, delayed examinations after 1 hour did not contribute to the diagnosis. The work of McCalley et al furthered the initial studies of Iturralde and Venter~in several areas. First, the procedural modifications introduced allowed for greater comfort in both administration of the radionuclide and the subsequent imaging protocol. Second, the imaging technique and diagnostic criteria were refined enabling more objective interpretation. Finally, these results lent further support to the contention that the radionuclide study is a more physiologic indicator of tubal function than the radiographic contrast study. Angtuaco et al studied the efficacyof radionu-

ovar

L ovary

u terus "vag i na

3 0 rain Fig 1. Normal radionuc|ide HSP. (Reprinted with permission. 4}

FERTILITY AND IMPOTENCE

125

study of Angtuaco et al also demonstrates the value of this test as follow-up to tubal surgery.

Dosimetry Radionuclide HSP is performed in women who are attempting pregnancy and there is obvious concern about radiation dosage to the ovaries. The calculation of radiation dosages depends on the initial assumptions concerning radionuclide percentage contacting the ovary and the contact half-time. Stabin points out that calculated dosage in rads can vary as much as 100-fold based on these assumptions.7 Technical factors, affecting both the radiologic and scintigraphic examinations, will greatly vary radiation dose, and should be optimized accordingly. McCalley et al4 have estimated an ovarian dose of 1.8 rad/mCi for radionuclide HSP, assuming that 5% of the administered dose resides on each ovary for the duration of decay, and based on data from computer-derived timeactivity curves. In a later submission by this group, this estimate was doubled. 5 Stabin, of the Oak Ridge Radiopharmaceutical Internal Dose Fig 2. Cornu cutoff sign. Note abrupt cutoff of activity in area of right cornu of uterus (arrow). Patient had obstruction o n right with patent hydrosalpinx on left at surgery. (Reprinted with permission. 4)

clide HSP in 13 infertile women who had undergone tubal surgery within the previous year for the correction of tubal obstruction6 (Table 1). Using a radionuclide method similar to that described by McCalley's group, 4 comparison was made with contrast HSP performed on the same day. In three cases, either the conventional or the radionuclide hysterosalpingogram was technically compromised. In eight cases, there was agreement between the two modalities, with tubal obstruction demonstrated in five cases and patency in three. In two cases of disagreement, bilateral patency was seen on the contrast study with complete obstruction on the radionuclide study. The investigators suggest that the scintigraphic diagnosis of functional obstruction was correct in one of the cases, while in the other it was due to misinterpretation of the scintigram (Fig 3). In addition to helping confirm previous work establishing a role for the radionuclide procedure in tubal disease, the

Fig 3. Technical pitfall. This delayed image shows peritoneal activity, which appears to come from both sides of the uterus (arrowheads). When correlated with the conventional HSP, spillage from the left was believed to have pooled in the region of the right adnexa, simulating patency. (Reprinted with permission. 6)

126

ZUCKIER AND STROBER

Information Center, has calculated a dose approximately threefold higher than McCalley's original value. 7 The gonadal radiation doses received during radionuclide HSP are comparable to those received during the radiographic contrast examination? Angtuaco et al have calculated an ovarian dose of 2.3 rad for radionuclide HSP and 2.37 rad for conventional contrast HSP~6

Perspective It is clear that radionuclide HSP allows the investigation of tubal patency in female infertility with ease of performance, patient comfort, and functional relevance. Furthermore, these goals are accomplished with radiation doses comparable to those received by contrast HSP. Nonetheless, radionuclide HSP continues to be underused at most centers. If the functional nature of radionuclide HSP could be rigorously shown to better predict outcome than the contrast study, then physicians may be willing to exchange the superior spatial resolution of contrast HSP for the functional superiority of radionuclide HSP. Because imaging in this procedure is performed within 1 hour of administration of radionuclide, it may also be possible to use a shorter-lived isotope, thereby reducing the radiation exposure to less than the radiologic procedure. Specific technical refinements, as well as an increased awareness on the part of nuclear medicine and referring physicians, may lead to more widespread use of radionuclide HSP. In the meanwhile, this examination should still be considered the procedure of choice in patients with iodinated contrast allergy and in other special circumstances. IMPOTENEE

Impotence is defined as the consistent inability to achieve or sustain an erection of sufficient rigidity for sexual intercourse. 8 To properly comprehend the diagnosis of this disorder, it is necessary to be familiar with the salient features of penile anatomy and physiology,8-12 and to consider the various etiologies of impotence and their evaluafion.

PenileAnatomy and Physiology Grossfeatures. The penis contains two paired intercommunicating corpora cavernosa, as well

as a single, ventrally placed corpus spongiosum. This latter structure encases the urethra and expands distally to form the glans penis. Each corpus is surrounded by a fibrous tunica albuginea, and all three corpora are encased by Buck's fascia, a dense fascial sheath. Vascular anatomy. In the understanding of erection, the vascular features of the penis are of foremost importance. 13'14The arterial supply originates from the internal pudendal artery, a branch of the internal iliac artery. After giving off a perineal artery branch, a short penile artery is formed, which ramifies into four branches, the dorsal, bulbar, urethral, and cavernous arteries. Among these, it is only the cavernous, or deep branch, that is involved in supplying the corpora cavernosa. The remaining three arteries supply other tissues of the penis and do not contribute substantially to the mechanism of erection. The paired deep cavernous arteries lead to multiple helicine arteries, so named because of their tortuous course. These pass through terminal arterioles to empty into the cavernous spaces, which fill with blood during erection. This unique vascular bed, discussed below, is specific to the penis and is responsible for its ability to achieve a turgid state. The venous drainage of the penis is threefold, with a superficial, intermediate, and deep system. Drainage of the corporal spaces is primarily via the intermediate system. In the distal penis, emissary veins pass through the fibrous tunica albuginea to connect the corporal spaces with the deep dorsal vein. This vein runs deep to Buck's fascia and superficial to the tunica albuginea, emptying into the pudendal or periprostatic venous plexus. In the proximal penis, the emissary veins form the cavernous vein, which drains through the internal pudendal vein. Both of these systems empty into the internal iliac veins. Physiology of erection. The sinusoidal circulation of the penis is of key importance in the formation of erection. 13 The initial stage in development of an erection is relaxation of the arterioles and sinusoids of the corpora cavernosa, which leads to an increased inflow of blood. With filling of the sinusoidal spaces, the emissary veins are passively compressed against the fibrous tunica albuginea (corporal veno-occlusive mechanism), leading to a secondary in-

FERTILITY AND IMPOTENCE

127

penis during sleep, the so-called nocturnal penile tumescence (NPT) test. It is used to verify occurrence of nocturnal erections, which normally occur three to four times nightly, during periods of REM sleep. In essence, the NPT examination evaluates erection in a situation where psychogenic factors have been bypassed by sleep. If erections occur, the examination suggests that the neurologic and vascular mechanisms required for erection are intact and that erectile failure is due to psychogenic causes. Conversely, an abnormal test implies an organic cause of impotence. Another functional office examination, entailing the injection of vasoactive agents into the corpora cavernosa, evaluates erection after elimination of both psychogenic and neurologic factors. Normally, when papaverine, phentolamine, or prostaglandin E 1 (PGE~) is injected directly into the corpora cavernosa, relaxation of the arterioles and sinusoids results in the development of a rigid erection. A normal erection in a patient who otherwise has erectile failure suggests presence of either psychogenic or neurologic impotence, while an abnormal examination suggests a vascular etiology, but does not differentiate between arterial and venous causes. A rare exception to this general rule occurs in extremely anxious patients, where psychological factors may suppress a normal erectile response, even in the absence of organic pathology.

crease in venous resistance and further rifling and rigidity of the penis. Finally, during the phase of rigid erection, the bulbocavernous reflex stimulates contraction of pelvic muscles, which briefly boosts intrapenile cavernous pressure to levels even greater than arterial systolic pressure. The chain of events leading to erection begins with psychologic factors, leading to transmission of parasympathetic impulses to the penis. The sinusoidal arterioles then relax, with subsequent filling of the sinusoids and passive impingement on the draining veins. Etiologies of impotence relate directly to potential interruptions in this chain of events and include psychogenic, neurologic, arterial, and venous abnormalities (Fig 4). Detumescence occurs after neurologically stimulated contraction of trabecular smooth muscle in the corpora cavernosa. This increases the tone of the arterioles and sinusoids, thereby reducing inflow of arterial blood and reversing the corporal veno-occlusive mechanism. With decreased inflow and free outflow of blood, baseline flaccidity returns.

Nonscintigraphic Evaluation of Impotence Functional evaluation. The various diagnostic tests used to evaluate the concatenated steps in erection vary in invasiveness and utility. 8'15-~~ A simple non-invasive examination involves monitoring the circumference and rigidity of the Alternate

REM Sleep

Vasoactive Agents

rect,, Pathways

Normal Erectile Pathway

Standard Assessment

Radionuclide Assessment

Psychological Stimulation

Neu I i Conduc~on ' ' ~ ' 1 = ~

Arterial Inflow

Patient History PsychometricTes~ng

ReflexTesting Biothedorfletry Evoked Potentials

Penile BloodPressure DuplexSono0raphy Artedography

NPT

~ v

Venous Stasis

~r Erection

DuplexSonography C,avernosometp/ Cavemesography

Patient History Strain-gaugeMeasurements

IntracavemosalInjection

Blood Pool (ArterialIndices) TracerWashout (Raccid) 9 Baseline - Post Ischemic

Bicod Pool (VenousIndices) TracerWashout (Erect)

Fig 4. Erectile pathways and their assessment. Flow chart illustrates normal and alternate pathways in the physiological and pharmacological development of erection, Both standard and scintigraphic methods of assessment have been charted under the positions corresponding to the information that they convey,

128

Arterial evaluation. The integrity of the arterial supply to the penis may also be evaluated by a group of examinations with a range of invasiveness. Penile blood pressure measurements can be obtained by use of a blood pressure cuff and a Doppler probe. These measurements are performed in the flaccid state and are usually compared with brachial arterial pressure to generate a penile/brachial index, which is norreally greater than 1. Various pelvic steal and hyperemia maneuvers may be performed to identify flow-related arterial insufficiency. Of the four major arteries supplying the penis, this test does not specifically evaluate the cavernous artery and may therefore fail to identify a localized abnormality of this crucial branch. In duplex sonography and pulsed Doppler, examination is performed both flaccid, and after induction of erection by vasoactive substances. The cavernous arteries are studied for changes in diameter and flow rate after erection and structural abnormalities of the corpora, such as fibrous areas, can be identified. Venous disease may also be inferred from the Doppler flow curves.

The most invasive arterial test is penile arteriography, which necessitates selective cannulation of the internal pudendal arteries. Intraarterial vasodilators and analgesics are often administered, as are intracavernous vasoactive agents. The examination is relatively painful, and arterial spasm may lead to false-positive findings. If well-defined lesions are identified, angioplasty can be attempted. In addition to the obstruction of larger arterial branches, some controversy exists as to the contribution of arteriolar abnormalities on the incidence of impotence. 21These may be difficult to assess using regular arteriologic technique. Venous evaluation. Two major examinations may be used to assess venous integrity. Peak flow velocities on Doppler sonography relate to venous resistance, and this examination can be used to evaluate for venous disease, as well as arterial insufficiency. A further method of evaluation of venous disease is by infusion cavernosometry and cavernosography. This entails the placement of bilateral butterfly needles into the penile cavernous spaces. One side is used for infusion of saline, and the second catheter is used to monitor intracavernosal pressures. Es-

ZUCKIER AND STROBER

sentially, this test consists of recording an infusion rate/pressure relationship during the induction and maintenance of erection. If a venous leak is detected, iodinated contrast may be administered via the infusing catheter, and radiographs are obtained to identify the sites of venous abnormalities.

Scintigraphic Examinations This finally leads us to the various scintigraphic techniques that have been used to evaluate impotence (Fig 4). The major approaches have been either blood pool studies, optimally with 99~Tc-labeled red blood cells (99mTc-RBC),2z or washout methods, chiefly using xenon-133 (mXe). These tests have been sporadically developed over the last 2 decades and have used a number of different combinations of radiotracers, routes of administration, and interventions. Although there is no uniformity of opinion in this field, a consensus is beginning to emerge as these techniques become more widespread. From the perspective of current knowledge, some of the early radionuclide studies appear poorly designed, often with inappropriate control and patient groups for the parameters studied. To a large degree, these design flaws are understandable, given that during this period, the separate contribution of arterial and venous disease to vasculogenic impotence was not clearly understood. 2 Blood pool indicators (Table 2). The concept of studying the penile blood pool was proposed and subsequently developed by Shirai et al in the early 1970s.23-26As the diagnosis and therapy of impotence has progressed, there has been a resurgence of interest in this methodology. An ideal blood pool radiotracer is a stably labeled radiopharmaceutical, dispersed throughout, but confined to within the vascular space. Assay of this radiotracer would then yield quantitative information on the relative blood volume in the area under investigation. As applied to the penis, this method entails labeling the systemic blood pool with a gamma emitter, such as 99~Tc.A probe or camera is then placed over the penis, which is usually shielded from surrounding background activity by a lead drape. Region-of-interest (ROI) analysis and background correction may also be performed

FERTILITY AND IMPOTENCE

129 Table 2. Blood Pool Measurements in Impotence Investigations Venous

Investigator

Tracer

Dose

Device

Shirai 23 Shirai 24 Shirai 2s Shirai 26 Fanous27 Siraj 28 Schwartz3~ Siraj 31 Kim 32 Schwartz 33

[~311]HSA l~3mln microcolloid [TC]O4 Tc-RBC (in vitro) [Tc]O,Tc-RBC (in vivro) Tc-RBC (in vivtro) Tc-RBC (in vivo) [Tc]O,Tc-RBC (in vivtro)

20-40 i~Ci 400 tLCi 150-700 ~Ci 180-495 ixCi 20 mCi 19 mCi 30 mCi 20 mCi 20 mCi 15-30 mCi

Probe Probe Probe Probe Camera Camera Camera Camera Camera Camera

Standard No No No Yes No No Yes No No Yes

Stimulation IV yohimbine IV yohimbine Visual Visual IV isoxsuprine IV isoxsuprine Visual & IC PAPA IC PAPA or PGE~ IC PAPA Visual & IC PAPA

Criteria of

Criteria of

Arterial Evaluation

VenousEvaluation

Qualitative Qualitative Qualitative PBV. RI PI PI. F1. F2. VRI PCF PI. F1 A1, A2 PCF, dCV

None None None None None None None Qualitative Vl, V2 Xenon washout

Abbreviations: HSA, human serum albumin; IC, intracavernosal; IV, intravenous; PAPA, papavarine; in vivtro, modified in vivo method. Abbreviations in criteria columns are defined in Table 3.

where indicated (Fig 5). Penile counts are acquired in the flaccid and erect states. Erection was originally achieved by visual sexual stimulation 25'26 or systemic (intravenous) vasodilators23'24'27-29;however, today intracavernosal injection of vasoactive drugs3~ is a more effective and reproducible method of achieving erection.

/

The resultant time-activity curve is visually inspected and numerical indices can be calculated (Fig 6, Table 3). It is also possible to generate absolute volume measurements by comparison to appropriate standards. 26'3~ The initial work by Shirai and Nakamura emphasized qualitative changes in the timeactivity curves, occurring with development of erection. 23zs Further refinement of this method also included a quantitative measure of the proportional increase in counts (post-erection/ pre-erection), as well as the absolute posterection volume, calculated with reference to a venous blood sample. 26Fanous et al also adopted a quantitative approach in their studies, by defining a penogram index, which represented the increment in counts after erection divided by the baseline counts ([post-erection- preerection]/pre-erection). 27 This measure correHP2 ~-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

~

HP1 + HP2 2 tu HP1

I, I

o

I

i~l_

I

v2

_l

I

o

I -10

I

I I

I

I

i

I

0 A2 SiJrrlulUS

10

20

A2+V2

30

TIME (minutes)

Fig 5. 99~rc-RBC blood pool acquisition ROI. Schematic representation of typical field of view during blood pool study. 1 and 2, penile ROI; 3, syringe; 4, background. (Reprinted with permission? ~}

Fig 6. Idealized time-activity curve (TAC) of penile blood pool activity (after Kim et aPZ). To standardize terminology, time of erectile stimulation has been set at 0, with prior time points described on a negative scale. A2 has been defined as the time when peak activity after stimulation occurs. Table 3 describes additional blood pool indices based on this nomenciature, some of which are indicated in the figure.

130

ZUCKIER AND STROBER

Table 3. Described Blood Pool indices Index

Value (see Fig 5)

Full Name

Investigator

PBV RI PI F1

Pooled blood volume Rate of increase Penogramindex Flow index 1

C(A2) normalized to venous standard C(A2)/C(0) [C(O) - C(-7.5)]/[Z lilac artery counts]

Shirai = Shirai = Fanous 27 Siraj z"

F2 VRI FI

Flow index 2 Vasodilator response index Flow index

[C(+2.5) - C(+7.5)]/1~ lilac artery counts] [F2-FlJ/F1 Same as VRI

Siraj ~ Siraj z8 Siraj z'

PCF HP1

Peak corporal f l o w Baseline activity

Peak dC/dt normalized to venous standard C(0)

Schwartz ~ Kim a2

HP2 A1 A2

Peak activity

C(A2) [HP2 - C ( - 1 0 ) ] / C ( - 10) See Fig 5

Kim ~ Kim 3z Kim 32

V1

[HP2 - C(A2 + 30)]/C(A2 + 30)

Kim a=

V2

Interval between peak counts (HP2) & half-peak

Kim ~

dCV

[HP1 + HP2]/2 Change in C(t) from 1 min before 1 min after peak

Schwartz ~

Time to reach peak (HP2)

Volume change

|C(A2)-C(O)]/C(O)

corporal flow, normalized to venous standard

lated well with the penile to brachial blood pressure index. Siraj et al added a vasodilator response ~ or flow31 index, which related to the relative difference in slopes of the time-activity curves before and after vasoactive medication was administered, normalized for counts in the lilac vessels. In the assessment of arterial insufficiency, this index is a logical approach to quantification of the rapid inflow that occurs during induction of erection. A similar approach has been used by Schwartz et al. 3~These investigators calculated absolute flow by imaging the penis and a 10-mL standard of venous blood during the attainment of erection (Fig 5). The change in penile counts with time was normalized according to the activity of the standard, thereby yielding absolute flow rates (this method assumes negligible venous leakage during the filling phase). The peak corporal flow was shown to correlate well with an angiographic index of arterial integrity. Patients with virtually normal arteries had mean peak corporal flows of 14.7 ___4.4 mL/min, while those with severe arterial disease had calculated values of 4.8 ___ 1.5 mL/min. As would be expected, no correlation was identified between peak corporal flow and intracorporal resistance, 34a measure of venous competence. The optimal method for evaluating arterial sufficiency with 99mTc-RBC has come full circle in the most recent publication by Schwartz et al. 33 The parameter that correlated best with angiographic score was the change in penile

blood volume from i minute before to 1 minute after time of peak inflow (r = .96). The investigators felt that this parameter reflected the ability to maintain inflow rates during the peak phase of tumescence. In essence, this sophisticated statistical investigation endorsed a methodology quite similar to that published by Shirai et al in 1976!26 While the blood pool examinations are primarily suited to evaluation of arterial sufficiency, Siraj et al have described the typical appearance of the time activity curve in venous incompetence, where the post-erection plateau in counts is not sustained. 31 Kim et al went one step further by numerically quantitating this disappearance of activity from the erect penis. 32 In addition to two arterial indices, they generated two venous washout indices, related to the fraction of activity remaining 30 minutes after peak erection and the time needed after peak erection to return half-way toward the baseline (Fig 6, Table 3). These indices were useful in differentiating patients with venous disease from those with arterial insufficiencyor no disease. There is no doubt as to the value of blood pool studies in the evaluation of arterial etiologies of impotence. As for the usefulness of the specific indices to diagnose and quantitate venous disorders, further study is needed. Washout indicators (Table 4). In the flaccid penis, the rate of washout of xenon reflects baseline penile perfusion, assuming adequate mixing of the radiotracer35 (Fig 7). Washout

FERTILITY AND IMPOTENCE

131

Table 4. Intracavernosal Washout Examinations Investigator Tracer

Route Dose (l~Ci)

Volume Erectile (mL) Device Stimulus

Nseyo zs

133Xe

SC

1,OOO-2,000

.1

Camera None

Lin 37

133Xe

SC

1,000-2,000

.1

Camera None

Nseyo 3s Haden 43

~33Xe 133Xe

JC IC

1,000-2,000 500-1,200

.1 .1-.2

Camera None Camera None

Yeh ~

133Xe

IC

1,000-2,000

.1

Camera None

Shirai 39 133Xe Wagner r176 133Xe Wagner 15 lZZXe

IC IC IC

200-300 300 2-400

NS .2-.3 NS

Probe Probe Probe

Visual Visual Visual

N

Average Age

Normal Arterial impotence Young normal Older normal Arterial impotence Unspecified impotence Normal Mixed impotence Neurogenic impotence Normal Venous impotence Normal Normal Normal Arterial impotence Venous impotence

3 8 10 11 10 3 6 14 5 12 21 5 4 NS NS NS

31 59 24 58 =58 NS 32 69 39 48 52 33 27 NS NS NS

5 11/15

53 51

Metz41

133Xe

IC

2-300

.2

Probe

Yeh az

13ZXe

IC

1,000-2,000

.1

Groshar as

TC-RBC (In vitro)

IC

Camera IC PGE1 Venous impotence 12/14 60 Nonvenous impotence 6 Combined Camera IC PAPA Venous impotence 7 45 Nonvenous impotence 13 Combined

2 • 500 / "

NS

Visual

Diagnosis

Peyronie's, normal Peyronie's, venous

Flaccid Flow (mL/100g/min) 7.5-14.2 _<4.9 9.5 • 1.7 9.4 • 2.7 <6 < 2.4-4.9 .7 _+ .6 .8 -+ .66 1.3 --- .54 5.4 • 2.3 2.4 • 1.3 2.0 • .7* 3-8 2.5-8 "Low . . . . "Same as normal"

2.1 • 2.2 9.4 • 9.3 NS NS

Erect Flow (mL/lg0 g/rain) ----

--

-43 • .7* 0-4

Decrease Further reduction" "Increases" "NormaIvenous closure" "insufficient venous closure" 7.5 -+ 5.6 2.2 -+ 1.0

Abbreviations: SC, subcutaneous: IC, intracavernosal. *Value standardized to partition coefficient of .7,

measurements during non-steady-state conditions, such as during penile blood volume expansion, do not simply measure penile blood flow, but are more complicated functions of several variables. Finally, once an erection is attained and a steady-state blood volume is again achieved, washout of activity reflects the level of penile perfusion present.

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Fig 7. Washout of l~Xe from the corpus cavernosum in flaccid state. Each datapoint represents the total counts recorded by gamma camera in the penile ROI for a 15-second time interval. Analysis of the 5- to 30-minute segment of the curve yielded a blood flow of 1.3/100 g/rain. (Reprinted with permission. 43)

Radioactive indicators, chiefly 133Xe, have been used to evaluate both the blood flow in the flaccid penis, after subcutaneous or intracavernosal injection, and the washout of activity during erection, reflecting the integrity of mechanisms for venous occlusion. To identify patients with venous disease, the latter application, because it is performed while the venous occlusive mechanism is normally engaged, appears the most promising. Subcutaneous 13~Xe. Two groups have studied the washout of 133Xe after subcutaneous injection into the flaccid penis at the level of the dorsal coronal s u l c u s . 36'37 In this steady-state condition, the rate of disappearance of xenon relates to the subcutaneous blood flow of the penis, albeit by branch arteries that do not supply the corpora cavernosa. Nonetheless, major arterial disease, affecting resting blood flow to the penis as a whole, would be identified. In 1984, Nseyo et al studied three control subjects and 16 patients, demonstrating an excellent correlation between the subcutaneous xenon washout test and the established techniques of penile arterial pulses and blood pressure measurements. 36It should be noted that these correlative examinations also measure global penile perfusion and do not specifically assess the cavernous artery. Some 5 years later, L i n e t al performed a similar procedure in 21 control

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subjects and 60 patients, demonstrating good correlation of this method with both arteriography and clinical findings.37 Clearance times greater than 7.5 or 8 minutes were determined to be abnormal and corresponded to flows of less than 6 or 7 mL/100 g/min. 36'~7 Subcutaneous 133Xeis limited because it does not specifically measure blood flow in the allimportant cavernosal arteries, and also because the penis is studied only in the flaccid state?8 For these reasons, the labeled blood pool technique would appear to be a more physiologic method of arterial evaluation. Intracavernosal lS3Xe with erection. Intracavernosal 133Xe injections, to determine cavernosal blood flow, were described in 1978 in another pioneering work by Shirai et al.39In five subjects with complete erections after visual sexual stimulation, intrapenile blood flow averaged 2.0 mL/100 g/min while flaccid and 43.0 mL/100 g/rain while erect, using a partition coefficient of 1. The apparent increase in penile blood flow with erection has not been confirmed by other groups. The same year, Wagner and Uhrenholdt presented conflicting data from a similar study in four normal volunteers.no A strain-gauge plethysmograph was used to monitor circumferential size of the penis and both flow and circumferential volumes were continuously recorded during and after erection. Visual sexual stimulation was continued until full erection was obtained. The investigators observed that penile blood flow decreased after visual sexual stimulation, declining from 3 to 8 mL/100 g/min in the flaccid state to 0 to 4 mL/100 g/min while erect. During detumescence, blood flow was initially elevated (20 to 75 mL/100 g/min), and subsequently decreased to the flaccid levels 2.5 to 4 minutes after termination of the visual stimulation. In 1983, this group published results of intracavernosal injection of xenon in patients with Peyronie's disease,41 a disorder that is frequently accompanied by impotence. In five patients with normal erectile function, normal venous closure was noted after onset of erection, similar to the finding previously noted in controls, n~ In 11 of 15 patients with impotence, visually stimulated erection paradoxically resulted in insufficient venous closure. Absolute numerical values were not stated.

ZUCKIER AND STROBER

More recently, Yeh et al studied intracavernosal penile xenon washout in patients with incomplete erectile response to the intracavernosal injection of PGE~, both before and after administration of this vasoactive agent. 42While patients with nonvenous disease, as assessed by other modalities, had a decrease in 133Xecorporeal clearance after PGEI administration, 12 of 14 patients with documented venous disease had a significant increase in xenon washout. As demonstrated above, the majority of investigators have found that erection normally resuits in decreased penile washout, while in patients with venous disease, an increase in washout occurs. Shirai's conflicting findings in normal patients 39 may be due to unsuspected venous disease in the control group; however, this would unlikely include all individuals studied. It has been suggested that Shirai's anomalous results may be due to a relatively short stimulation period ~5 and lack of plethysmographic monitoring. ~8 Under these conditions, there may not have been rigid erection throughout the measurement period) 3 This could conceivably result in increased penile inflow without complete engagement of the venous occlusive mechanisms. Alternatively, an immediate posterection state may have prevailed and would explain the similarities between Shirai's "erect" measurements and the findings of Wagner and Uhrenholdt in the initial post-erection period.no Wagner has also hypothesized that the Japanese researchers' method of injecting local anesthesia before xenon could potentially interfere with neural regulation of venous closure, resulting in the described findings.~5 lntracavernosal I33Xe without erection. While it seems most profitable to study rates of washout of intracavernosal xenon in the erect state, where the disparity between normals and patients with venous disease would be accentuated, some investigators have focused their attention on washout in the flaccid penis. Assuming a steady-state condition, this measurement would reflect baseline cavernosal perfusion. Wagner found that impotent patients with arterial disease had a lower flow rate than normal subjects at rest. 15 In patients with venous disease, the basal flow in the flaccid state was the same as in normal subjects. Haden et al also studied intracavernosal xe-

FERTILITY AND IMPOTENCE

non retention in the flaccid state (Fig 7), performing their study in a group of elderly patients with impotence, as well as in normal controls and patients with neurogenic impotence. 43 Except for the group of patients with spinal cord injury and neurogenic impotence, individuals were not segregated according to the etiology of their disorder. No correlation was found between rate of washout and degree of impotence, leading the investigators to conelude that they could not find any value for flaccid measurements. An objection to this study has been raised regarding the 15-minute delay between injection of xenon and initiation of measurements, although the authors have defended their actions.44 In a pilot trial of three patients, Nseyo et al reported what they believed was a markedly prolonged half-time after intracorporeal xenon injections in the flaccid s t a t e . 36 While these values are considerably longer than rates of washout from subcutaneous penile injections, they actually overlap washout rates determined by other investigators (see Table 4). In contrast, Yeh et al noted an unanticipated abnormality of flaccid washout in patients with v e n o u s d i s e a s e . 4z'45 In their initial studies of 12 controls and 21 patients with venous disease, prolonged xenon retention was seen in patients with venous disease as compared with normal subjects (half-times of 24.4 _-_+10.7 minutes v 10.7 + 4.6 minutes in controls). They attributed this unexpected finding to incompetent venous valves with reflux back into the penis. It is still unclear as to what effect venous disease has on xenon washout in the flaccid state, and there is considerable variation in values described by different investigators. This question is of theoretical and physiologic importance; however, washout in the erect penis appears to be the optimal method of detecting venous incompetence. In a variation on the flaccid washout test, Wagner has described a postocclusive washout test where intracavernosal xenon washout is measured both before and after 5 minutes of cuff-induced penile ischemia. 15 This penile "stress test" artifically stimulates rapid flow in the penile arteries and serves to identify patients with arterial disease where augmented flow cannot occur.

133

99mTc-RBC washout. An interesting hybrid examination was recently performed by Groshar et al, using 99mTc-RBC to measure rates of washout. 46 To establish clearance half-times in both the flaccid and erect states, two separate direct intracorporeal injections of 0.5 mCi of a u t o l o g o u s 99mTc-RBC were performed. While no statistically significant difference was noted between 13 normal subjects and seven patients with venous leak when measured in the flaccid state (202 +- 139 seconds v 92 --+ 35 seconds), papaverine-induced erection produced a significant increase in half-time in normal subjects (2,892 --- 1,899 seconds) as compared with patients with venous incompetence (213 __-123 seconds). This approach, if it can be validated, may provide a more convenient and simple means of determining cavernosal washout than xenon studies. It may also be possible to perform combination washout and blood pool studies using injections of only one isotope. It is interesting to note both the flaccid and erect half-times measures are several-fold shorter than their counterparts in xenon washout studies. A second difference is the reported slight increase in half-time of washout in patients with venous disease after erection. As noted above, other groups using xenon have noted a decrease in washout time after erection in patients with venous incompetence. While the authors have shown that 99"Tc-RBC washout appears to effectively identify patients with venous disease on the basis of their erect half-times, discrepancies with xenon washout must caution us as to the exact physical correlates of what we are measuring. Combined Test

Two groups have recently reported use of a combined blood pool and xenon washout study for the evaluation of penile blood flow.33'47 In theory, this would allow the calculation of simultaneous arterial inflow and venous outflow during the attainment of erection (Fig 8). Furthermore, the calculated inflow rate could be corrected for underestimation caused by venous outflow to obtain a more accurate value. Miraldi et al briefly described a method using 99mTCRBC and 133Xewashout with erection induced by intracavernosal papaverine. 47 Twenty patients were studied and the investigators claim

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that specific patterns for the various etiologies of impotence were obtained. Schwartz and Graham have published a method where blood pool tests were performed on separate occasions using 99~Tc-RBC and 133Xe (nine patients) or simultaneously using 99mTc-RBC and 127Xe (five patients). 33 Correction of the inflow rate to account for simultaneous venous outflow actually decreased the correlation between the calculated inflow and arteriographic scoring. Why this correction would actually degrade the correlation is not obvious. As the majority of the data analyzed in this report come from patients sequentially studied, spanning intervals of many months, underlying hemodynamic changes over the time period may have rendered the "corrections" imperfect. An additional factor may relate to methodologic problems with the calculated rate of corporal outflow. The intracorporeal resistance, a measure of venous leak, u correlated poorly with the calculated rate of corporal outflow at time of peak corporal inflow (r = .24). Neither the raw data nor individual descriptions

Fig 8. Dual-isotope technique showing graphs of intracorporal inflow, outflow, and volume. (A) Normal study. (B) Venous leek. (C) intermediate arteries and competent veins, (Reprinted with permission, ~)

of the 14 patients studied are included in the report, and it is therefore difficult to postulate why the xenon study failed to predict the magnitude of venous leak. It does appear that significant venous disease was not well represented in the study group, and these results may not be representative of the method's ability to detect and quantitate significant venous abnormalities in the general population. Miraldi et al ~ in their most recent work studied 14 subjects by simultaneous 99~Tc-RBC and ]33Xe washout. Based on these data, peak arterial and venous flows were successful in discriminating between arterial insufficiency, venous leak, and normal. The dual-isotope approach is a major advance in the scintigraphic analysis of impotence, by allowing simultaneous calculation of changes in both inflow and outflow of penile blood. While the high level of technical difficulty may confine this examination to a research setting, nonetheless, this technique will afford us a better understanding of the interrelationship of various vascular factors on the etiology of impo-

FERTILITY AND IMPOTENCE

135

tence and will shed light on the physiology of erection in general.

Miscellaneous ~nTc-RBC blood pool cavernosography.

As a

replacement to contrast cavernosography, Shirai's group attempted to image the corpus cavernosum with 99mTc-RBC and a gamma camera fitted with pinhole collimator. 49Three impotent patients were studied in whom no organic abnormalities were found. Although the investigators were optimistic in their ability to visualize the penis, the limited intrinsic resolution of the method may be responsible for its failure to catch on as an anatomic modality. Flow studies. Another penile investigation with limited success was the use of [99mTc]O4 flow studies to demonstrate graft patency following penile vascular bypass procedures. 5~ Six patients were studied at varying times after successful bypass grafting from the femoral artery to the corpus cavernosum. In two patients, the flow images did not d e a r l y delineate either the vascular graft or the penis, while in four some degree of visualization was noted. At present, results of such a flow study might be improved with concurrent use of intracavernous vasoactive agents. Nonetheless, the availability of duplex sonography has successfully filled this diagnostic need. Facey et al have studied dynamic images in impotent patients to assess blood flow in the iliac arteries and the penis after the injection of [99mTc]OL29 While no specific details are given, this technique may offer some complimentary benefit in the assessment of arterial disease and can be performed in the course of a blood pool study without additional radiation exposure or patient discomfort.

Dosimetry Blood pool studies. Penile blood pool studies, using 99~Tc-RBC, have identical dosimetry as commonly performed cardiac and hemangioma blood pool studies. Commonly accepted per-millicurie dosimetry values are 55 mrad to the blood and 19 mrad to the whole body. s~'Sz Xenon washout studies. Assuming a blood flow of 1 mL/100 mg/min, H a d e n et al have calculated a radiation dose of approximately 2.1 rad/mCi to the injection site. 43 The dose to the testes and whole body are similar to those of intravenous injections and are quoted as .065 and 0.12 mrad/mCi, respectively. Wagner has stated that a dose of 300 ~Ci is equivalent to 1.2 mrad, although it is unclear as to what target volume he is referring to. 4~As with radionuclide HSP discussed earlier, assumptions regarding the rate of transit or washout of radiopharmaceutical, which in turn depend on the quality and duration of erection, have tremendous implications on dosimetry in penile washout studies. FUTURE PROSPECTS

The scintigraphic tests for infertility and impotence are still evolving. The relative indications and value of the examinations have not been definitively ascertained; however, their quantitative and physiologic nature add a unique dimension to the diagnosis and evaluation of these disorders. 53 With development of new and sophisticated treatment modalities, the need for these attributes will certainly increase. ACKNOWLEDGMENT

Dr Zuckier would like to expresshis sincere appreciation to the library staff and their efforts in retrieving ever-more obscure medicalreferences.

REFERENCES tium-99m hysterosalpingographyin infertility:An accurate 1. SwerdloffRS, Overstreet JW, Sokol RZ, et al: Infertilalternative to contrast hysterosalpingography.Radiographity in the male. Ann Intern Med 103:906-919,1985 2. HilsonAJW, LewisCA: Radionuclidestudies in impoits 9:115-128,1989 7. Stabin ML: Radiation dosimetry in radionuclide hystence. Semin Nucl Med 21:159-164,1991 terosalpingographywith technetium-99m. J Nucl Med 30: 3. Iturralde M, Venter PF: Hysterosalpingo-radionudide scintigraphy(HERS). SeminNuel Med 11:301-314,1981 415-416, 1989 8. Krane RJ, Goldstein I, Tejada IS: Impotence.N Engl J 4. McCalleyMG, Braunstein P, Stone S, et al: RadionuMed 321:1648-1657,1989 clide hysterosalpingographyfor evaluation of fallopiantube 9. WagnerG: Erection. Anatomy,in WagnerG, Green R patency. J Nucl Med 26:868-874,1985 (eds): Impotence. Physiological,Psychological,Surgical Di5. Stone SC, McCalleyM, Braunstein P, et al: Radionuclide evaluation of tubal function. Fertil Steril 43:757-760, agnosis and Treatment. New York, NY, Plenum, 1981 pp 1985 7-24 6. Angtuaco TL, Boyd CM, London SN, et al: Techne10. Wagner G: Erection. Physiologyand endocrinology,

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ZUCKIER AND STROBER

31. Siraj QH, Bomanji J, Akhtar MA, et al: Quantitation of pharmacologically-induced penile erections: the value of radionuclide phailography in the objective evaluation of erectile haemodynamics. Nucl Med Commun 11:445-458, 1990 32. Kim SC, Kim KB, Oh CH: Diagnostic value of the radioisotope erection penogram for vasculogenic impotence. J Urol 144:888-893, 1990 33. Schwartz AN, Graham MM: Combined technetium radioisotope penile plethysmography and xenon washout: A technique for evaluating corpora cavernosal inflow and outflow during early tumescence. J Nucl Med 32:404-410, 1991 34. Freidenberg DH, Berger RE, Chew DE, et al: Quantitation of corporeal venous outflow resistance in man by corporeal pressure flow evaluation. J Urol 138:533-538, 1987 35. Lassen NA, Lindbjerg J, Munck O: Measurement of blood-flow through skeletal muscle by intramuscular injection of xenon-133. Lancet 1:686-689, 1964 36. Nseyo UO, Wilbur HJ, Kang SA, et al: Penile xenon (133Xe) washout: A rapid method of screening for vasculogenic impotence. Urology 23:31-34, 1984 37. Lin SN, Chang LS, Liu RS, et ai: Diagnosis of vasculogenic impotence: Combination of penile xenon-133 washout and papaverine tests. Urology 34:28-32, 1989 38. Mellinger BC, Krysiewicz S: The role of imaging in the diagnostic evaluation of impotence. A JR 154:1347, 1990 (reply) 39. Shirai M, Ishii N, Mitsukawa S, et al: Hemodynamic mechanism of erection in the human penis. Arch Androi 1:345-349, 1978 40. Wagner G, Uhrenholdt A: Blood flow measurement by the clearance method in the human corpus cavernosum in the flaccid and erect states, in Zorgniotti AW, Rossi G (eds): Vasculogenic Impotence. Springfield, IL, Thomas, 1980, pp 41-46 41. Metz P, Ebbehoj J, Uhrenholdt A, et al: Peyronie's disease and erectile failure. J Urol 130:1103-1104, 1983 42. Yeh SH, Liu RS, Chen KK, et al: Diagnosis of venous leakage by Xe-133 corporeal clearance after intraeavernous injection of prostaglandin E1 in poor responding patients. Nucl Med Commun 13:28-32, 1992 43. Haden HT, Katz PG, Mulligan T, et al: Penile blood flow by xenon-133 washout. J Nucl Med 30:1032-1035, 1989 44. Villanueva-Meyer J: Penile blood flow by xenon-133 washout. J Nucl Med 31:246, 1990 45, Yeh SH, Liu RS, Lin SN, et al: Corporeal 133Xe washout for detecting venous leakage in impotence. Nucl Med Commun 12:203-209, 1991 46. Groshar D, Lidgi S, Frenkel A, et al: Radionuclide assessment of penile corporal venous leak using technetium99m-labeled red blood cells (Tc-RBC). J Nucl Med 33:4951, 1992 47. Miraldi F, Nelson AD, Jones WT, et al: A noninvasive technique for the evaluation of male impotence. J Nucl Med 30:784, 1989 48. Miraldi F, Nelson AD, Jones WT, et al: A dualisotope technique for the evaluation of penile blood flow during tumescence. J Nucl Med 33:41-46, 1992 49. Shirai M, Ishii N, Mitsukawa S, et ai: Visualization of the human cavernosum penis by using 99m-Tc-labeled

FERTILITY AND IMPOTENCE

autologous red blood cells. Tohoku J Exp Med 120:199-200, 1976 50. Casey WC, Zucker MI: Technetium-99 pelvic scan. Use in follow-up of penile revascularization bypass operations. Urology 14:465-466, 1979 51. Malamud H: Dosimetry of 99mTc-labeled blood pool scanning agents. Clin Nucl Med 3:420-421, 1978

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52. Srivastava SC, Chervu LR: Radionuclide-labeled red blood cells: Current status and future prospects. Semin Nucl Med 14:68-82, 1984 53. Chaudhuri TK, Fink S, Burger RH, et al: Nuclear penogram: Non invasive technique to monitor and record effect of pharmacologically-induced penile erection in impotence therapy. Urology 35:98, 1990 (letter)