Hypospermia

Last updated
-spermia,
Further information: Testicular infertility factors
Aspermia—lack of semen; anejaculation
Asthenozoospermia—sperm motility below lower reference limit
Azoospermia—absence of sperm in the ejaculate
Hyperspermia—semen volume above upper reference limit
Hypospermia—semen volume below lower reference limit
Oligozoospermia—total sperm count below lower reference limit
Necrozoospermia—absence of living sperm in the ejaculate
Teratozoospermia—fraction of normally-formed sperm below lower reference limit

Hypospermia is a condition in which a man has an unusually low ejaculate (or semen) volume, less than 1.5 mL. It is the opposite of hyperspermia, which is a semen volume of more than 5.5 mL. [1] It should not be confused with oligospermia, which means low sperm count. Normal ejaculate when a man is not drained from prior sex and is suitably aroused is around 1.5–6 mL, although this varies greatly with mood, physical condition, and sexual activity. Of this, around 1% by volume is sperm cells. The U.S.-based National Institutes of Health defines hypospermia as a semen volume lower than 2 mL on at least two semen analyses. [2]

Contents

The presence of high levels of fructose (a sugar) is normal in the semen and originates almost entirely from the seminal vesicles. The seminal vesicles, which are major contributors to ejaculate volume, render semen viscous with a pH of 7.2–7.8. [1] An acidic seminal pH (pH < 7.2) suggests damage to the seminal vesicles and an alkaline seminal pH (pH > 8) suggests prostatic involvement. [2] In addition, low fructose may indicate problems in the prostate, while low semen pH may indicate problems related to the [seminal vesicles]. Obstruction of the seminal vesicles results in low semen volumes since they normally produce 70% of the seminal plasma.

Signs and symptoms

The most common sign of hypospermia is a low volume of semen during ejaculation. [1] The diagnosis is confirmed when one has a semen volume of less than 2.0 mL on at least two successive spermograms. [2] If hypospermia is caused by retrograde ejaculation, sign include cloudy urine after orgasm. There may not be any symptoms of hypospermia unless it is caused by an abnormality. [2]

Causes

Even though there are numerous causes for hypospermia, all of the known contributing factors can be placed into two major distinct categories: [2]

Dysfunction of ejaculatory reflex

Examples of dysfunction of ejaculatory reflex include:

Retrograde ejaculation

  • This means that the sperm is produced in the testes but on its way out, it gets misdirected into the bladder rather than coming out through the urethra. This can lead to a low volume of semen (hypospermia) or no semen production (aspermia). Structural or functional damage to the bladder neck muscle causes the backflow of semen during the ejaculation.[ medical citation needed ] Nerve damage caused by medical conditions such as diabetes or multiple sclerosis can affect the function of bladder neck muscle. Also, surgery or trauma along with the medications used for hypertension and benign prostatic hyperplasia can contribute to bladder neck problems. Retrograde ejaculation can be diagnosed by the presence of sperm in the urine. [2]

Anatomical defects

Examples of anatomical defects include:

Congenital absence of vas deferens and seminal vesicle

  • In the male reproductive system, there are structures such as vas deferens and seminal vesicles which play an important role in transportation and production of semen or ejaculate. Abnormalities or absence of these structures can lead to low volume of semen and infertility in males. This condition can also be caused by the mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which encodes for chloride channel protein. [2]

Blockage of the ejaculatory duct

  • This is a condition that is caused by obstruction of either one or both ejaculatory ducts leading to hypospermia. The etiology of ejaculatory duct obstruction can be congenital or acquired. The presence of a prostatic cysts, ejaculatory duct stones, or post surgical inflammation of the duct can block the normal flow of semen through the reproductive tract. [2]

Hypogonadism

  • Insufficient or low levels of testosterone in the body can affect the proper functioning of the male reproductive structures and thus lead to decreased secretions or hypospermia. Long-term exposure to drugs with anti-androgen properties (e.g. spironolactone) can also lead to infertility or low volume of semen. [2] Testosterone is produced by the testes and can be used to diagnose hypogonadism. [3]

Drugs

Drugs can have various types of impact on the male body, side effects of medications may affect male fertility, spermatogenesis, and sexual function. Drugs can affect sperm parameters by inhibiting normal exocrine functions of the testes which can lead to a decrease in production of sperm, or by creating hormone imbalances. [4] For an example, anti-androgenic drugs like spironolactone, cimetidine, and ketoconazole can disrupt androgens in the glands and seminal tract to cause a decrease in production of semen volume. [2] Furthermore, common drugs used to treat hypertension and benign prostatic hyperplasia (increased size of prostate) like tamsulosin are attracted to dopamine and serotonin receptors in the brain to cause a decrease in sperm volume through a mechanism that remains unknown. [2]

Certain medications in the following classes of drugs may affect spermatogenesis or sperm parameters*:

Certain medications in the following classes of drugs may affect male sexual libido or sexual function**:

*"For most of the drugs that are likely to affect spermatogenesis and/or sperm parameters, the levels of scientific evidence are still insufficient (with the exception of Sirolimus, Sulfasalazine, exogenous testosterone, Finasteride and Cyproterone acetate, for which the levels of evidence are higher). In some cases, data in men do not even exist, and the toxicity of a drug for the male reproductive organs is determined solely on the basis of animal models." [5]

**"For a certain number of pharmaceutical molecules that are likely to affect the sexual function of men being treated, the actual imputability of the drug is often difficult to pinpoint owing to the effect of the illness itself on sexuality (cardiovascular disease and erectile dysfunction; depressive illness and loss of desire, etc.)" [5]

Furthermore, hyperthyroidism, an excess of thyroid hormones, has been associated with reduced semen volume, reduced sperm density, motility, and morphology. Studies in humans show that an excess of circulating thyroid hormones during thyrotoxicosis results in asthenozoospermia, oligozoospermia, and teratozoospermia. These abnormalities frequently associate with semen alterations like reduced semen volume. [6]

Lifestyle factors

Alcohol use

Lifestyle factors, such as substance use or adiposity, can play a detrimental role in the quality of the semen. One study examining the consequences of alcohol consumption and its effect on semen quality concluded that alcohol intake can lead to a negative effect on semen volume in daily alcohol consumers. However, occasional or moderate use of alcohol was observed to not have an adverse effect on the semen. [7]

Body mass index (BMI)

A body mass index (BMI) level not within normal range can also affect semen quality negatively. Being underweight, presented by a low BMI value, was observed in an analysis to decrease the total sperm count and semen volume. No significant changes were observed in sperm concentration and motility due to a low BMI. However, due to the lack of raw data, further research is needed to clarify the role of BMI in semen quality. [8] On the other hand, an overweight (BMI of 25.9–29.9) or obese status (BMI over 30) is similarly associated with low semen quality through a decrease of semen volume, concentration, motility, count, and morphology. Alteration of sex hormone levels were also concluded to result from a high BMI status, with affected hormones such as inhibin B or testosterone observed to decrease in concentration, whereas estradiol was increased. The reduction in hormone levels can subsequently result in being diagnosed with hypogonadism. [9]

Trace minerals

An inadequate level of essential trace minerals in the body can further compromise semen quality. A significantly lower zinc plasma concentration value within the semen was observed in infertile males. Supplementation with zinc could benefit sperm quality by increasing the semen volume and improving sperm motility and morphology. [10] Notably, no significant effects on sperm concentration, count, or sperm viability have been conclusively observed. The likely benefits of zinc in the semen stem from its multifaceted contributions to the stability of the membranes and sperm chromatin. [10] In addition to zinc, nutritional deficiencies or excess intake of selenium is also associated with impaired semen quality. However, in moderate levels, the antioxidant properties of selenium, likely due to an increase in glutathione peroxidase-1 activity (enzyme protecting from oxidative damage) and reduction of reactive oxygen species (ROS) production, may be recommended for supplementation. [5]

Dietary pattern

In general, a healthy dietary pattern is encouraged, and food modifications may be useful in promoting sperm quality. Some studies have concluded that intake of antioxidants is associated with better sperm parameters as high concentrations of reactive oxygen species can negatively affect the sperm. Consumption of an adequate portion of vegetables and fruits, dietary fibers, omega-3, poultry, and low-fat dairy products may help to lessen risk of male infertility. On the other hand, diets that have been negatively associated with male infertility include high intake of potatoes, soy foods, coffee, alcohol, and sweetened beverages. [11] According to a review, higher consumers of cola showed a statistically significant decrease in semen volume. [12] The high starch levels in potatoes promotes oxidative stress along with risk of inflammation from a resulting high glycemic index. Meanwhile, processed meats can possibly contain xenoestrogens and may compromise semen quality. However, additional research is warranted prior to recommending a set dietary regimen in regard to improving sperm parameters. Currently, the only general recommendation that can be made is to adhere to a healthy dietary pattern such as the DASH diet or Mediterranean diet. [5]

As low density of the sperm population is usually associated with infertility, hypospermia becomes an infertility issue when one is also identified to have oligospermia. Further semen analysis may be needed prior to being identified as oligospermic. When a semen analysis does indicate abnormal results, lifestyle factors recommendations prior to a new semen sample include a nutritional diet, as well as limitations on smoking and alcohol use. A cold bath and removal of tight-fitted underwear apparel may also be recommended within the month prior to re-examination. [1]

Etiological testing

Ultrasound imaging

Imaging the urogenital system via an ultrasound is the first-line imaging test for hypospermia. This assessment looks out for testicular degeneration, testicular anomalies, and carry out a detailed study of the deep genital tract and glands using a high endorectal probe frequency. This examination makes it possible to visualize the vas deferens over their pelvic path and therefore to diagnose possible agenesis (absence of cells within organs) on portions not accessible to clinical examination. [2]

Seminal chemistry

Seminal chemistry is a second-line examination needed in the event of suspicion of abnormalities of the excretory genital tract. This examination consists of measuring biochemical markers of the prostate, seminal vesicles and epididymis and seminal plasma, which can indicate the level of damage in these areas and help locate the level of lesions in the cases of hypospermia. The biochemical markers that are measured are alpha-glucosidase (in the epididymis), fructose (in the seminal vesicles) and zinc, citric acid and/or acid phosphatase (for the prostate). The levels of these biological markers are lowered in a variable manner depending on the level of damage to the genital tract. [2]

CTFR screening

Depending on the severity of the hypospermia (volume ≤ 1 mL) a molecular study of the CFTR gene may be performed. This is done by a molecular "screening" method (high performance liquid chromatography under denaturing conditions (D-HPLC) followed by sequencing of the exons of interest, allowing to detect nearly 95% of mutations in this gene, and even discover new mutations. After this molecular screening step, if variants of the CFTR gene are detected, the geneticist will use computer databases to distinguish whether this nucleotide variant corresponds to a polymorphism of the CFTR gene (without consequence on the function of the CFTR protein) or to a real mutation. [2]

Semen analysis

A common route to diagnosis for hypospermia that may be requested for is a semen analysis. To obtain the most fresh specimen collection, a semen sample is obtained through the process of masturbation in the setting of a laboratory. An abstinence period of 3–5 days is recommended prior to collection of samples. If a semen analysis cannot be completed, an alternative route to collecting a semen is through coitus interruptus into a bottle. Normally, a typical specimen displays coagulation after ejaculation due to the presence of enzymes within the seminal vesicle, followed by liquification in approximately 30 minutes. [1]

Urine collection

Furthermore, when the semen volume is low, less than 1 ml, a urine specimen should be collected immediately after masturbation to search for sperm in the urine. [13] Two days before the urine sample is collected, one is required to drink an alkalinized water to allow the sperm cells to survive. After this preliminary preparation step, urine collection is done in a fractional way: the first milliliters of urine are collected and analyzed in isolation through centrifugation and examination under a microscope. The presence of substantial sperm in the post-ejaculatory urine specimen confirms the diagnosis of partial retrograde ejaculation, a dysfunction of the ejaculatory reflex and a known cause of hypospermia. [2]

Unfortunately, even after thorough etiological assessments, an assessor many come to the conclusion of no known etiological cause to explain one's diagnosis of hypospermia. The significance of these idiopathic hypospermia cases are currently unknown and requires more research in the future. [2]

Treatment

Although there are no existing medications on the market for the treatment of hypospermia, some medications and herbal medications have off label uses which can aid in the treatment of this condition and should be considered as soon as possible. According to a review, the use of maca has shown to improve semen volume through an unclear mechanism. [14] In addition, some classes of medications that have been studied include both antidepressants and vessel dilators. Use of pharmacological therapy is uncommon thus individual must rely on psychosexual therapy. [15] Psychosexual therapy addresses issues focused on sexual skills/techniques, self esteem, performance anxiety and interpersonal conflict. [16] Furthermore, according to a review, longer abstinences from sexual intercourse has been associated with increases in sperm count and semen volume. [17]

According to a review, the management for hypospermia will depend upon the etiology of the disease. Studies have shown that functional retrograde ejaculation can be treated with oral pharmacotherapy such as imipramine and pseudoephedrine which can prevent the backflow of semen and stimulate ejaculation. In the case of structural retrograde ejaculation, pharmacotherapy might not work but surgical procedures can fix the bladder neck problem. [18]

The blockage of the ejaculatory duct can be treated via transurethral resection of the ejaculatory duct (TURED) and is indicated for people with low sperm volume. [19] TURED has been shown to improve the volume of semen in men with ejaculatory duct obstruction leading to significant improvement in the fertility rate. [20]

Hormonal abnormalities caused by either primary or secondary hypogonadism can be treated with off-label use of oral clomiphene citrate which has been shown to increases the level of testosterone in the body. Administration of exogenous testosterone for the treatment of hypogonadism has shown to a have negative impact on the process of spermatogenesis. [21]

Abnormalities in the seminal vesicle and vas deferens usually don't respond well to surgeries or medications. In such situations, sperm can be extracted along with assisted reproductive technologies (ARTs) such as intrauterine insemination (IUI), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI) for successful conception. [22] These procedures can be very costly. [21]

Prevention

A study was done to compare the sperm outcomes of individuals with or without infection of the human papilloma virus (HPV), which currently affects 79 million Americans. The study concluded that individuals who had not been infected with HPV had higher rates of sperm motility, functionality, and concentration of sperm. [23] This study suggests that individuals who do not contract HPV or who are vaccinated against HPV have better fertility outcomes than those who are not vaccinated or who have contracted HPV. Vaccination against HPV with Gardasil9 can be administered by hospitals, clinics or most pharmacies in 3 doses ideally at age 11–12 in both girl and boys, but can be taken up to age 45 per Center of Disease Control (CDC) guidelines. [24]

See also

Related Research Articles

<span class="mw-page-title-main">Prostate</span> Gland of the male reproductive system in most mammals

The prostate is both an accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemically, and physiologically. Anatomically, the prostate is found below the bladder, with the urethra passing through it. It is described in gross anatomy as consisting of lobes and in microanatomy by zone. It is surrounded by an elastic, fibromuscular capsule and contains glandular tissue, as well as connective tissue.

<span class="mw-page-title-main">Retrograde ejaculation</span> Redirection of ejaculated semen into the urinary bladder

Retrograde ejaculation occurs when semen which would be ejaculated via the urethra is redirected to the urinary bladder. Normally, the sphincter of the bladder contracts before ejaculation, sealing the bladder which besides inhibiting the release of urine also prevents a reflux of seminal fluids into the male bladder during ejaculation. The semen is forced to exit via the urethra, the path of least resistance. When the bladder sphincter does not function properly, retrograde ejaculation may occur. It can also be induced deliberately by a male as a primitive form of male birth control or as part of certain alternative medicine practices. The retrograde-ejaculated semen, which goes into the bladder, is excreted with the next urination.

<span class="mw-page-title-main">Seminal vesicles</span> Pair of simple tubular glands posteroinferior to the urinary bladder of male mammals

The seminal vesicles are a pair of convoluted tubular glands that lie behind the urinary bladder of some male mammals. They secrete fluid that partly composes the semen.

<span class="mw-page-title-main">Epididymis</span> Tube that connects a testicle to a vas deferens

The epididymis is an elongated tubular structure attached to the posterior side of each one of the two male reproductive glands, the testes. It is a single, narrow, tightly coiled tube in adult humans, 6 to 7 meters in length. It connects the testicle to the vas deferens in the male reproductive system. The epididymis serves as an interconnection between the multiple efferent ducts at the rear of a testicle (proximally), and the vas deferens (distally). Its primary function is the storage, maturation and transport of sperm cells.

<span class="mw-page-title-main">Vas deferens</span> Part of the male reproductive system of many vertebrates

The vas deferens, with the more modern name ductus deferens, is part of the male reproductive system of many vertebrates. The ducts transport sperm from the epididymis to the ejaculatory ducts in anticipation of ejaculation. The vas deferens is a partially coiled tube which exits the abdominal cavity through the inguinal canal.

<span class="mw-page-title-main">Ejaculatory duct</span> Male anatomical structures

The ejaculatory ducts are paired structures in male reproductive system. Each ejaculatory duct is formed by the union of the vas deferens with the duct of the seminal vesicle. They pass through the prostate, and open into the urethra above the seminal colliculus. During ejaculation, semen passes through the prostate gland, enters the urethra and exits the body via the urinary meatus.

<span class="mw-page-title-main">Male reproductive system</span> Reproductive system of the human male

The male reproductive system consists of a number of sex organs that play a role in the process of human reproduction. These organs are located on the outside of the body and within the pelvis.

<span class="mw-page-title-main">Human reproductive system</span> Organs involved in reproduction

The human reproductive system includes the male reproductive system which functions to produce and deposit sperm; and the female reproductive system which functions to produce egg cells, and to protect and nourish the fetus until birth. Humans have a high level of sexual differentiation. In addition to differences in nearly every reproductive organ, there are numerous differences in typical secondary sex characteristics.

<span class="mw-page-title-main">Azoospermia</span> Medical condition of a man whose semen contains no sperm

Azoospermia is the medical condition of a man whose semen contains no sperm. It is associated with male infertility, but many forms are amenable to medical treatment. In humans, azoospermia affects about 1% of the male population and may be seen in up to 20% of male infertility situations in Canada.

Terms oligospermia, oligozoospermia, and low sperm count refer to semen with a low concentration of sperm and is a common finding in male infertility. Often semen with a decreased sperm concentration may also show significant abnormalities in sperm morphology and motility. There has been interest in replacing the descriptive terms used in semen analysis with more quantitative information.

Aspermia is the complete lack of semen with ejaculation. It is associated with infertility.

Male infertility refers to a sexually mature male's inability to impregnate a fertile female. In humans it accounts for 40–50% of infertility. It affects approximately 7% of all men. Male infertility is commonly due to deficiencies in the semen, and semen quality is used as a surrogate measure of male fecundity. More recently, advance sperm analyses that examine intracellular sperm components are being developed.

Anejaculation is the pathological inability to ejaculate despite an erection in males, with (orgasmic) or without (anorgasmic) orgasm.

<span class="mw-page-title-main">Reproductive medicine</span> Branch of medicine

Reproductive medicine is a branch of medicine concerning the male and female reproductive systems. It encompasses a variety of reproductive conditions, their prevention and assessment, as well as their subsequent treatment and prognosis.

<span class="mw-page-title-main">Semen analysis</span> Scientific analysis of semen

A semen analysis, also called seminogram or spermiogram, evaluates certain characteristics of a male's semen and the sperm contained therein. It is done to help evaluate male fertility, whether for those seeking pregnancy or verifying the success of vasectomy. Depending on the measurement method, just a few characteristics may be evaluated or many characteristics may be evaluated. Collection techniques and precise measurement method may influence results.

Semen quality is a measure of male fertility, a measure of the ability of sperm in semen to accomplish fertilization. Semen quality involves both sperm quantity and quality. Semen quality is a major factor for fertility.

<span class="mw-page-title-main">Human penis</span> Human male external reproductive organ

In human anatomy, the penis is an external male intromittent organ that additionally serves as the urinary duct. The main parts are the root (radix); the body (corpus); and the epithelium of the penis including the shaft skin and the foreskin (prepuce) covering the glans penis. The body of the penis is made up of three columns of tissue: two corpora cavernosa on the dorsal side and corpus spongiosum between them on the ventral side. The human male urethra passes through the prostate gland, where it is joined by the ejaculatory duct, and then through the penis. The urethra traverses the corpus spongiosum, and its opening, the meatus, lies on the tip of the glans penis. It is a passage both for urination and ejaculation of semen.

<span class="mw-page-title-main">Semen</span> Reproductive biofluid of male or hermaphroditic animals

Semen, also known as seminal fluid, is an organic bodily fluid created to contain spermatozoa. It is secreted by the gonads and other sexual organs of male or hermaphroditic animals and can fertilize the female ovum. Semen is produced and originates from the seminal vesicle, which is located in the pelvis. The process that results in the discharge of semen from the urethral orifice is called ejaculation. In humans, seminal fluid contains several components besides spermatozoa: proteolytic and other enzymes as well as fructose are elements of seminal fluid which promote the survival of spermatozoa, and provide a medium through which they can move or "swim". The fluid is adapted to be discharged deep into the vagina, so the spermatozoa can pass into the uterus and form a zygote with an egg.

<span class="mw-page-title-main">Ejaculation</span> Euphoric stimulative semen discharge of the male reproductive tract

Ejaculation is the discharge of semen from the male reproductive tract as a result of an orgasm. It is the final stage and natural objective of male sexual stimulation, and an essential component of natural conception. Ejaculation can occur spontaneously during sleep, and is a normal part of human sexual development. In rare cases, ejaculation occurs because of prostatic disease. Anejaculation is the condition of being unable to ejaculate. Ejaculation is usually very pleasurable for men; dysejaculation is an ejaculation that is painful or uncomfortable. Retrograde ejaculation is the condition where semen travels backwards into the bladder rather than out of the urethra.

Ejaculatory duct obstruction (EDO) is a pathological condition which is characterized by the obstruction of one or both ejaculatory ducts. Thus, the efflux of semen is not possible. It can be congenital or acquired. It is a cause of male infertility and/or pelvic pain. Ejaculatory duct obstruction must not be confused with an obstruction of the vas deferens.

References

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  3. ↑ Bassas Arnau, Lluís (2009). "[Exploration of testicular function]". Endocrinologia y Nutricion. 56 (1): 18–31. doi:10.1016/S1575-0922(09)70190-1. ISSN   1575-0922. PMID   19627705.
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  5. 1 2 3 4 Salas-Huetos, Albert; James, Emma R.; Aston, Kenneth I.; Jenkins, Timothy G.; Carrell, Douglas T. (2019). "Diet and sperm quality: Nutrients, foods and dietary patterns". Reproductive Biology. 19 (3): 219–224. doi:10.1016/j.repbio.2019.07.005. ISSN   2300-732X. PMID   31375368. S2CID   199387538.
  6. ↑ La Vignera, Sandro; Vita, Roberto (2018). "Thyroid dysfunction and semen quality". International Journal of Immunopathology and Pharmacology. 32: 2058738418775241. doi:10.1177/2058738418775241. ISSN   2058-7384. PMC   5946587 . PMID   29737216.
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  20. ↑ Coppens, L. (1997). "[Diagnosis and treatment of obstructive seminal vesicle pathology]". Acta Urologica Belgica. 65 (2): 11–19. ISSN   0001-7183. PMID   9324904.
  21. 1 2 Pan, Michael M.; Hockenberry, Mark S.; Kirby, Edgar W.; Lipshultz, Larry I. (2018). "Male Infertility Diagnosis and Treatment in the Era of In Vitro Fertilization and Intracytoplasmic Sperm Injection". Medical Clinics of North America. 102 (2): 337–347. doi:10.1016/j.mcna.2017.10.008. PMID   29406062.
  22. ↑ Cissen, Maartje; Bensdorp, Alexandra; Cohlen, Ben J; Repping, Sjoerd; de Bruin, Jan Peter; van Wely, Madelon (2016). Cochrane Gynaecology and Fertility Group (ed.). "Assisted reproductive technologies for male subfertility". Cochrane Database of Systematic Reviews. 2016 (2): CD000360. doi:10.1002/14651858.CD000360.pub5. PMC   10335364 . PMID   26915339.
  23. ↑ Weinberg, May; Sar-Shalom Nahshon, Chen; Feferkorn, Ido; Bornstein, Jacob (2020). "Evaluation of human papilloma virus in semen as a risk factor for low sperm quality and poor in vitro fertilization outcomes: a systematic review and meta-analysis". Fertility and Sterility. 113 (5): 955–969.e4. doi: 10.1016/j.fertnstert.2020.01.010 . PMID   32386620. S2CID   218585082.
  24. ↑ "HPV Vaccine Recommendations | CDC". www.cdc.gov. 2021. Retrieved 2021-08-04.{{cite web}}: CS1 maint: url-status (link)
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