Many oral treatments have been studied, but results so far have been mixed. Some consider the use of nonsurgical approaches to be "controversial".

Collagenase clostridium histolyticum (marketed as Xiaflex by [Auxilium]), a drug originally approved by the FDA to treat Dupuytren's contracture, is now an FDA-approved injectable drug for treatment of Peyronie's disease. The drug is reported to work by breaking down the excess collagen in the penis that causes Peyronie's disease.

Vitamin E supplementation has been studied for decades, and some success has been reported in older trials, but those successes have not been reliably repeated in larger, newer studies. A combination of Vitamin E and colchicine has shown some promise in delaying progression of the condition.

Some newer agents targeting the basic mechanisms of inflammation have been studied in larger clinical trials. These include potassium para-aminobenzoate (Potaba), pentoxifylline (acting through TGFβ1 inhibition), and Coenzyme Q10.

The efficacy of Interferon-alpha-2b in the early stages of the disease has been reported in recent publications, but it was found to be less effective in cases where calcification of the plaque had occurred in common with many treatments.

Surgery, such as the "Nesbit operation" (which is named after Reed M. Nesbit (1898–1979), an American urologist at University of Michigan), is considered a last resort and should only be performed by highly skilled urological surgeons knowledgeable in specialized corrective surgical techniques. A penile prosthesis may be appropriate in advanced cases.

Paget's disease of the breast is a type of cancer of the breast. Treatment usually involves a lumpectomy or mastectomy to surgically remove the tumour. Chemotherapy and/or radiotherapy may be necessary, but the specific treatment often depends on the characteristics of the underlying breast cancer.

Invasive cancer or extensive ductal carcinoma "in situ" is primarily treated with modified radical mastectomies. The procedure consists in the removal of the breast, the lining over the chest muscles and a part of the lymph nodes from under the arm. In cases of noninvasive cancers, simple mastectomies are performed in which only the breast with the lining over the chest muscles is removed.

Patients suffering from cancer that has not spread beyond the nipple and the surrounding area are often treated with breast-conserving surgery or lumpectomy. They usually undergo radiation therapy after the actual procedure to prevent recurrence. A breast-conserving surgery consists in the removal of the nipple, areola and the part of the breast that is affected by cancer.

In most cases, adjuvant treatment is part of the treatment schema. This type of treatment is normally given to patients with cancer to prevent a potential recurrence of the disease. Whether adjuvant therapy is needed depends upon the type of cancer and whether the cancer cells have spread to the lymph nodes. In Paget's disease, the most common type of adjuvant therapy is radiation following breast-conservative surgery.

Adjuvant therapy may also consist of anticancer drugs or hormone therapies. Hormonal therapy reduces the production of hormones within the body, or prevents the hormones from stimulating the cancer cells to grow, and it is commonly used in cases of invasive cancer by means of drugs such as tamoxifen and anastrozole.

Five bisphosphonates are currently available. In general, the most commonly prescribed are risedronic acid, alendronic acid, and pamidronic acid. Etidronic acid and other bisphosphonates may be appropriate therapies for selected patients but are less commonly used. None of these drugs should be used by people with severe kidney disease.

- Etidronate disodium The approved regimen is once daily for six months; a higher dose is more commonly used. No food, beverage, or medications should be consumed for two hours before and after taking. The course should not exceed six months, but repeat courses can be given after rest periods, preferably of three to six months duration.

- Pamidronate disodium in intravenous form: the approved regimen uses an infusion over four hours on each of three consecutive days, but a more commonly used regimen is over two to four hours for two or more consecutive or nonconsecutive days.

- Alendronate sodium is given as tablets once daily for six months; patients should wait at least 30 minutes after taking before eating any food, drinking anything other than tap water, taking any medication, or lying down (patient may sit).

- Tiludronate disodium are taken once daily for three months; they may be taken any time of day, as long as there is a period of two hours before and after resuming food, beverages, and medications.

- Risedronate sodium tablet taken once daily for 2 months is the prescribed regimen; patients should wait at least 30 minutes after taking before eating any food, drinking anything other than tap water, taking any medication, or lying down (patient may sit).

- Zoledronic acid is given as an intravenous infusion; a single dose is effective for two years. This is recommended for most people at high risk with active disease.

Calcitonin, also called calcitonin-salmon, is a synthetic copy of a polypeptide hormone secreted by the ultimobranchial gland of salmon. Miacalcin is administered by injection, three times per week or daily, for 6–18 months. Repeat courses can be given after brief rest periods. Miacalcin may be appropriate for certain patients, but is seldom used. Calcitonin is also linked to increased chance of cancer. Due to the increased risk of cancer, the European Medicines Agency (EMA) recommended that calcitonin be used only on a short-term basis for 3 conditions for which it had previously been approved in the European Union: Paget's disease, acute bone loss resulting from sudden immobilization, and hypercalcemia caused by cancer.

The EMA said it based its recommendations on a review of the benefits and risks of calcitonin-containing medicines. Conducted by the agency's Committee for Medicinal Products for Human Use (CHMP), the review encompassed available data from the companies that market these drugs, postmarketing safety data, randomized controlled studies, 2 studies of unlicensed oral calcitonin drugs, and experimental cancer studies, among other sources.

CHMP found that "a higher proportion of patients treated with calcitonin for long periods of time develop cancer of various types, compared with patients taking placebo." The increase in cancer rates ranged from 0.7% for oral formulations to 2.4% for the nasal formulation. CHMP concluded that the benefits of calcitonin for osteoporosis did not exceed the risks. The nasal spray's only indication is for osteoporosis, thus justifying the drug's removal from the market.

As a solution for injection or infusion, calcitonin should be administered for no more than 4 weeks to prevent acute bone loss resulting from sudden immobilization, and normally for no more than 3 months to treat Paget's disease, the EMA said. The agency did not specify a time frame for the short-term use of calcitonin for treating hypercalcemia caused by cancer.

The principal treatment of chordee is surgery in infancy, usually by a pediatric urologist. With chordees caused by circumcision, the preferred method of surgical treatment is a z-plasty. The preferred time for surgery is between the ages of 6 and 18 months and correction is usually successful.

There are several treatment options for penile cancer, depending on staging. They include surgery, radiation therapy, chemotherapy, and biological therapy. The most common treatment is one of five types of surgery:

- Wide local excision—the tumor and some surrounding healthy tissue are removed

- Microsurgery—surgery performed with a microscope is used to remove the tumor and as little healthy tissue as possible

- Laser surgery—laser light is used to burn or cut away cancerous cells

- Circumcision—cancerous foreskin is removed

- Amputation (penectomy)—a partial or total removal of the penis, and possibly the associated lymph nodes.

Radiation therapy is usually used adjuvantly with surgery to reduce the risk of recurrence. With earlier stages of penile cancer, a combination of topical chemotherapy and less invasive surgery may be used. More advanced stages of penile cancer usually require a combination of surgery, radiation and chemotherapy.

In addition to all the above, treatment of the underlying disease like brucellosis, is important to limit disease recurrence.

The main treatment for isolated epispadias is a comprehensive surgical repair of the genito-urinary area usually during the first 7 years of life, including reconstruction of the urethra, closure of the penile shaft and mobilisation of the corpora. The most popular and successful technique is known as the modified Cantwell-Ransley approach. In recent decades however increasing success has been achieved with the complete penile disassembly technique despite its association with greater and more serious risk of damage.

Most doctors consider this a normal physiological phenomenon and advise against treatment.

The condition may be treated with surgery. There are several different techniques to treat this condition. Threading a suture through the lower membrane, and then tying a tight knot around the frenulum itself is a procedure that minimises invasive action. After a few days the frenulum will weaken and eventually break apart to allow the prepuce to fully retract. Other procedures involve the cutting of the skin and require the use of sutures to help in the healing process. Stretching exercises and steroid creams may also be helpful. Alternatively, it may be treated by a reparative plastic surgery operation called a frenuloplasty, or by complete circumcision including resection of the frenulum (frenectomy).

Paraphimosis can be avoided by bringing the foreskin back into its normal, forward, non-retracted position after retraction is no longer necessary (for instance, after cleaning the glans penis or placing a Foley catheter). Phimosis (both pathologic and normal childhood physiologic forms) is a risk factor for paraphimosis; "physiologic" phimosis resolves naturally as a child matures, but it may be advisable to treat "pathologic" phimosis via long-term stretching or elective surgical techniques (such as preputioplasty to loosen the preputial orifice or circumcision to amputate the foreskin tissue partially or completely).

The foreskin responds to the application of tension to cause expansion by creating new skin cells though the process of mitosis. The tissue expansion is permanent. Non-surgical stretching of the foreskin may be used to widen a narrow, non-retractable foreskin. Stretching may be combined with the use of a steroid cream. Beaugé recommends manual stretching for young males in preference to circumcision as a treatment for non-retractile foreskin because of the preservation of sexual sensation.

Paraphimosis can often be effectively treated by manual manipulation of the swollen foreskin tissue. This involves compressing the glans and moving the foreskin back to its normal position, perhaps with the aid of a lubricant, cold compression, and local anesthesia as necessary. If this fails, the tight edematous band of tissue can be relieved surgically with a dorsal slit or circumcision. An alternative method, the Dundee technique, entails placing multiple punctures in the swollen foreskin with a fine needle, and then expressing the edema fluid by manual pressure. According to Ghory and Sharma, treatment by circumcision may be elected as "a last resort, to be performed by a urologist". Other experts recommend delaying elective circumcision until after paraphimosis has been resolved.

The presence of three factors for the prognosis has been suggested, whether there is a palpable mass of the disease, whether lymph nodes are positive and whether there is an underlying malignant cancer.

If there is none of these, the five- and 10-year survival is 85% and 80% respectively, with adjuvant chemotherapy even 95% and 90%. If there is a palpable mass, it is 32% and 31% respectively, with adjuvant chemotherapy (40% and 35%).

Positive lymph-nodes have been positively associated with a palpable mass and affect the prognosis to be now just 28% survival after 10 years (vs 79% without palpable mass and without affected lymph-nodes). Involvement of the lymph nodes does not directly cause any harm, but is merely an indicator of systemic spread.

Furthermore, patients with an identifiable associated underlying breast tumor have a survival rate of 38-40% at five years and a survival rate of 22-33% at 10 years. The death rate of metastatic breast carcinoma in patients with mammary Paget's disease and underlying cancer is 61.3%, with a 10-year cumulative survival rate of 33%.

Treatment involves biopsy of the lesion to identify extent of dysplasia. Complete excision of the lesion is sometimes advised depending on the histopathology found in the biopsy. Even in these cases, recurrence of the erythroplakia is common and, thus, long-term monitoring is needed.

Initial treatment in adults often involves simply pulling back the foreskin and cleaning the penis.

Surgical methods range from the complete removal of the foreskin to more minor operations to relieve foreskin tightness:

- Dorsal slit (superincision) is a single incision along the upper length of the foreskin from the tip to the corona, exposing the glans without removing any tissue.

- Ventral slit (subincision) is an incision along the lower length of the foreskin from the tip of the frenulum to the base of the glans, removing the frenulum in the process. Often used when frenulum breve occurs alongside the phimosis.

- Preputioplasty, in which a limited dorsal slit with transverse closure is made along the constricting band of skin, can be an effective alternative to circumcision. It has the advantage of only limited pain and a short time of healing relative to circumcision, and avoids cosmetic effects.

- Circumcision is sometimes performed for phimosis, and is effective, but this was becoming less common as of 2012.

While circumcision prevents phimosis, studies of the incidence of healthy infants circumcised for each prevented case of phimosis are inconsistent.

Initially, an evaluation of malignancy is always indicated. If no abnormality is found, then a surgical duct excision may resolve the symptoms. Treatment also depends on whether single-duct or multiple-duct discharge is present, and whether the symptoms of nipple discharge are distressing to the patient. In some cases, there may be no need for any further intervention; in others, microdochectomy or a total duct excision may be appropriate. If the patient wishes to conserve the ability to breastfeed and only single-duct discharge is present, then ductoscopy or galactography should be considered in view of performing a localised duct excision. Once the cause of the nipple discharge is found, it will be treated by the health provider who will evaluate:

- Whether changing any medicine that has caused the discharge is appropriate

- Whether any lumps should be removed

- Whether some or all of the breast ducts should be removed

- If a prescription for cream to treat skin changes around the nipple will be helpful

- If medicines to treat a health condition are required

If all the tests are normal, treatment may not be necessary. A follow up mamogram mammogram and physical exam may be prescribed within 1 year.

Physiologic phimosis, common in males 10 years of age and younger, is normal, and does not require intervention. Non-retractile foreskin usually becomes retractable during the course of puberty.

If phimosis in older children or adults is not causing acute and severe problems, nonsurgical measures may be effective. Choice of treatment is often determined by whether circumcision is viewed as an option of last resort to be avoided or as the preferred course.

The FDA does not recommend alternative therapies to treat sexual dysfunction. Many products are advertised as "herbal viagra" or "natural" sexual enhancement products, but no clinical trials or scientific studies support the effectiveness of these products for the treatment of erectile dysfunction, and synthetic chemical compounds similar to sildenafil have been found as adulterants in many of these products. The United States Food and Drug Administration has warned consumers that any sexual enhancement product that claims to work as well as prescription products is likely to contain such a contaminant.

Because hormone treatment rarely achieves average size, several surgical techniques similar to phalloplasty for penis enlargement have been devised and performed; but they are not generally considered successful enough to be widely adopted and are rarely performed in childhood.

In extreme cases of micropenis, there is barely any shaft, and the glans appears to sit almost on the pubic skin. From the 1960s until the late 1970s, it was common for sex reassignment and surgery to be recommended. This was especially likely if evidence suggested that response to additional testosterone and pubertal testosterone would be poor. With parental acceptance, the boy would be reassigned and renamed as a girl, and surgery performed to remove the testes and construct an artificial vagina. This was based on the now-questioned idea that gender identity was shaped entirely from socialization, and that a man with a small penis can find no acceptable place in society.

Johns Hopkins Hospital, the center most known for this approach, performed twelve such reassignments from 1960 to 1980, most notably that of David Reimer (whose penis was destroyed by a circumcision accident), overseen by John Money. By the mid-1990s, reassignment was less often offered, and all three premises had been challenged. Former subjects of such surgery, vocal about their dissatisfaction with the adult outcome, played a large part in discouraging this practice. Sexual reassignment is rarely performed today for severe micropenis (although the question of raising the boy as a girl is sometimes still discussed.) (See "History of intersex surgery" for a fuller discussion.)

A treatment option for micropenis is the insertion of a subcutaneous soft silicone implant under the penile skin. The procedure was developed by urologist James J. Elist.

The PDE5 inhibitors sildenafil (Viagra), vardenafil (Levitra) and tadalafil (Cialis) are prescription drugs which are taken orally.

A cream combining alprostadil with the permeation enhancer DDAIP has been approved in Canada as a first line treatment for erectile dysfunction.

One of the following medications maybe injected into the penis: papaverine, phentolamine, and prostaglandin E1.

Even with successful surgery, patients may have long-term problems with:

- incontinence, where serious usually treated with some form of continent urinary diversion such as the Mitrofanoff

- depression and psycho-social complications

- sexual dysfunction

Extramammary Paget's disease is usually seen in isolation and is associated with an underlying invasive malignancy about 12% of the time. It is associated with an underlying adnexal malignancy about 24% of the time. Paget's disease of the breast is almost always associated with an underlying invasive malignancy, i.e. breast cancer (e.g. mammary ductal carcinoma).

Treatment of small melanomas is often not necessary, but large tumors can cause discomfort and are usually surgically removed. Cisplatin and cryotherapy can be used to treat small tumors less than 3 centimeters, but tumors may reoccur. Cimetidine, a histamine stimulator, can cause tumors to regress in some horses, but may take up to 3 months to produce results and multiple treatments may be needed throughout the horse's life. There are few viable treatment options for horses with metastatic melanoma. However, gene therapy injections utilizing interleukin-12 and 18-encoding DNA plasmids have shown promise in slowing the progression of tumors in patients with metastatic melanoma.

Since Krukenberg tumors are secondary (metastatic), management might logically be driven by identifying and treating the primary cancer. The optimal treatment of Krukenberg tumors is unclear. The role of surgical resection has not been adequately addressed but if metastasis is limited to the ovaries, surgery may improve survival. The role of chemotherapy and/or radiotherapy is uncertain but may sometimes be beneficial.

Paget's disease of the vulva, a rare disease, may be a primary lesion or associated with adenocarcinoma originating from local organs such as the Bartholin gland, the urethra, or the rectum and thus be secondary. Patients tend to be postmenopausal.

Paget's disease of the penis may also be primary or secondary, and is even rarer than genital Paget’s disease in women. At least one case has been misdiagnosed as Bowen's disease. Isolated Paget's disease of the penis is extremely rare.